Cephalosporins

ABSTRACT

Novel syn isomers of 3-alkoxymethyl or 3-alkylthio-methyl-7-[2-(2-amino-4-thiazolyl)-2-oximino-acetamido]-cephalosporanic acid compounds of the formula ##STR1## wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, acyl of an organic carboxylic acid of 1 to 18 carbon atoms and alkoxy carbonyl of 2 to 6 carbon atoms, A is selected from the group consisting of hydrogen, alkali metal, alkaline earth metal, --NH 4 , magnesium, non-toxic, pharmaceutically acceptable organic amine and an easily cleavable ester group, Ra is selected from the group consisting of alkyl of 1 to 6 carbon atoms optionally interrupted with a heteroatom, alkenyl and alkynyl of 2 to 6 carbon atoms and optionally substituted aralkyl of 7 to 12 carbon atoms, n is 0,1 or 2, X&#39; is selected from the group consisting of oxygen and sulfur optionally oxidized to sulfoxide or sulfone and their non-toxic, pharmaceutically acceptable acid addition salts having antibiotic activity and their preparation.

PRIOR APPLICATION

This application is a division of U.S. patent application Ser. No.393,761 filed Jun. 30, 1982 now U.S. Pat. No. 4,992,431 which is adivision of U.S. patent application Ser. No. 234,327 filed Feb. 13,1981, now abandoned.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I' and their non-toxic, pharmaceutically acceptable acidaddition salts and a novel process for their preparation.

It is another object of the invention to provide novel antibioticcompositions and to provide a novel method of combatting bacterialinfections in warm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of the syn isomers of 3-alkoxymethyl or3-alkylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-oximino-acetamido]cephalosporanicacid compounds of the formula ##STR2## wherein R is selected from thegroup consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl andalkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, acylof an organic carboxylic acid of 1 to 18 carbon atoms and alkoxycarbonyl of 2 to 6 carbon atoms, A is selected from the group consistingof hydrogen, alkali metal, alkaline earth metal, --NH₄, magnesium,non-toxic, pharmaceutically acceptable organic amine and an easilycleavable ester group, Ra is selected from the group consisting of alkylof 1 to 6 carbon atoms optionally interrupted with a heteroatom, alkenyland alkynyl of 2 to 6 carbon atoms and optionally substituted aralkyl of7 to 12 carbon atoms, n is 0,1 or 2, X' is selected from the groupconsisting of oxygen and sulfur optionally oxidized to sulfoxide orsulfone and their non-toxic, pharmaceutically acceptable acid additionsalts.

Among the preferred compounds of the invention are the syn isomers ofcompounds of the formula ##STR3## wherein A, n and R have the abovedefinition X is selected from the group consisting of oxygen and sulfurand Ra is selected from the group consisting of alkyl of 1 to 6 carbonatoms, alkenyl and alkynyl of 2 to 6 carbon atoms and optionallysubstituted aralkyl of 7 to 12 carbon atoms and their non-toxic,pharmaceutically acceptable acid addition salts.

Examples of suitable groups of R are (a) alkyl of 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl,pentyl, isopentyl, sec-pentyl, tert.-pentyl, neo-pentyl, hexyl,isohexyl, sec-hexyl and tert.-hexyl (b) alkenyl of 2 to 6 carbon atomssuch as vinyl, allyl, 1-propenyl, butenyl, pentenyl and hexenyl, (c)alkynyl of 2 to 6 carbon atoms such as ethynyl, propargyl and butynyl,(d) cycloalkyl of 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl and (e) acyl of an organic carboxylic acid of1 to 18 carbon atoms such as acetyl, propionyl, butyryl, valeryl,hexanoyl, acryloyl, crotonoyl, benzyol, carbamoyl and alkoxycarbonylsuch as methoxycarbonyl and ethoxycarbonyl.

The above groups a to d and certain groups of e are optionallysubstituted with at least one member of the group consisting of carboxyloptionally salified or esterified; alkoxycarbonyl of 2 to 6 carbon atomssuch as methoxycarbonyl and ethoxycarbonyl; carbamoyl; dimethylcarbomyl;amino; dialkylamino of 1 to 6 carbon atoms such as dimethylamino anddiethylamino; alkylamino of 1 to 6 carbon atoms such as methylamino;halogen such as chlorine, bromine and iodine; alkoxy of 1 to 6 carbonatoms such as methoxy, ethoxy and propoxy; alkylthio of 1 to 6 carbonatoms as methylthio and ethylthio; aryl such as phenyl; arylheterocyclic such as tetrazolyl; arylthio such as optionally substitutedphenylthio; arylheterocyclicthio such as tetrazolylthio andthiadiazolylthio optionally substituted with alkyl of 1 to 6 carbonatoms such as methyl. The groups of d) and some of e) may be substitutedwith alkyl as defined in a.

Examples of A are hydrogen; alkali metals such as sodium, potassium andlithium; alkaline earth metals such as calcium; magnesium; --NH₄ ; andnon-toxic, pharmaceutically acceptable organic amines such asmethylamine, propylamine, trimethylamine, diethylamine, triethylamine,N,N-dimethyl-ethanolamine, tris-(hydroxymethyl)-aminomethane,ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine,benzylamine, procaine, lysine, arginine, histidine andN-methylglucamine.

Examples of A as an easily cleavable esters are methoxymethyl,ethoxymethyl, isopropoxymethyl, α-methoxyethyl, α-ethoxyethyl,methylthiomethyl, ethylthiomethyl, isopropylthiomethyl,pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl,isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl,tert.-butylcarbonyloxymethyl, hexadecanoyloxymethyl, propionyloxyethyl,isovaleryloxyethyl, 1-acetyloxyethyl, 1-propionyloxyethyl,1-butyryloxyethyl, 1-tert.-butylcarbonyloxyethyl, 1-acetyloxypropyl,1-hexadecanoyloxyethyl, 1-propionyloxypropyl, 1-methoxycarbonyloxyethyl,methoxycarbonyloxymethyl, 1-acetyloxybutyl, 1-acetyloxyhexyl,1-acetyloxyheptyl, phthalidyl, 5,6-dimethoxyphthalidyl,tert.-butylcarbonylmethyl, allyl, 2-chloroallyl, methoxycarbonylmethyl,benzyl and tert.-butyl.

Other easily cleavable ester groups for A are methoxyethoxymethyl,dimethylaminoethyl, cyanomethyl, tert.-butyloxycarbonylmethyl,2,2-ethylenedioxyethyl, cyanoethyl, 2,2-dimethoxyethyl,2-chloroethoxymethyl, 2-hydroxyethoxyethyl, 2,3-epoxypropyl,3-dimethylamino-2-hydroxypropyl, 2-hydroxyethyl,2-methylamino-ethoxymethyl, 2-aminoethoxymethyl,3-methoxy-2,4-thiadiazol-5-yl, 2-tetrahydropyranyl, 2-methoxyprop-2-yl,1-hydroxyprop-2-yl, isopropyl, carbamoylmethyl, chloromethyl,2-chloroethyl, acetylmethyl, 2-methylthioethyl and thiocyanatomethyl.

Still further easily cleavable ester groups for A are2-chloro-1-acetyloxyethyl, 2-bromo-1-acetyloxyethyl,2-fluoro-1-acetyloxyethyl, 2-methoxy-1-acetyloxyethyl,2-methyl-1-acetyloxypropyl, 2-acetyloxyprop-2-yl,1-methoxyacetyloxyethyl, 1-acetylcarbonyloxyethyl,1-hydroxyacetyloxyethyl, 1-formylcarbonyloxyethyl,1-(2-thienyl)-carbonyloxyethyl, 1-(2-furyl)-carbonyloxyethyl,1-(5-nitro-2-furyl)-carbonyloxyethyl, 1-(2-pyrrolyl)-carbonyloxyethyl,1-(propionyloxycarbonyloxyethyl), 1-(propyloxycarbonyloxy)-ethyl,1-(isopropyloxycarbonyloxy)-ethyl, 1-(methoxyethoxycarbonyloxy)-ethyl,1-(allyloxycarbonyloxy)-ethyl, 1-(2,3-epoxy)-propyloxycarbonyloxyethyl,1-(2-furyl)-methoxycarbonyloxyethyl,1-(2-fluoro)-ethoxycarbonyloxyethyl, 1-(methoxycarbonyloxy)-propyl,2-(methoxycarbonyloxy)-prop-2-yl, (methoxycarbonyloxy)-chloromethyl,1-(methoxycarbonyloxy)-2-chloro-ethyl,1-(methoxycarbonyloxy)-2-methoxy-ethyl and1-(methoxycarbonyloxy)-1-allyl.

Examples of Ra are the substituents a, b and c of the definition of Rabove and especially preferred are methyl, ethyl, propyl, isopropyl,allyl, methoxymethyl and ethoxymethyl. Among the preferred aralkylgroups of Ra are benzyl and phenylethyl optionally substituted with atleast one member of the group consisting of carboxy, amino, aminoalkylof 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, dialkylamino of 1to 6 carbon atoms and dialkylaminoalkyl of 1 to 6 carbon atoms such asdimethylaminoethyl.

The compounds of formula I' have a free amino group which can besalified with a non-toxic, pharmaceutically acceptable acid such asmineral acids like phosphoric acid, sulfuric acid, hydrochloric acid andhydrobromic acid and organic acids such as acetic acid, trifluoroaceticacid, maleic acid, tartaric acid, citric acid, methanesulfonic acid,benzenesulfonic acid and p-toluene sulfonic acid.

Among the preferred compounds of formula I are those wherein R isselected from the group consisting of hydrogen and alkyl of 1 to 4carbon atoms optionally substituted with amino or carbonyl free salifiedor esterified and those wherein Ra is alkyl of 1 to 6 carbon atoms andthe compounds of formula I wherein Ra is methyl and n is 0.

Another preferred group of compounds of the invention ion are synisomers of compounds of the formula ##STR4## wherein R, n, X and Ra havethe above definitions, B is selected from the group consisting ofhydrogen and optionally subsituted alkyl of 1 to 5 carbon atoms and D isselected from the group consisting of optionally substituted alkyl andalkoxy of 1 to 15 carbon atoms, especially 1 to 5 carbon atoms and theirnon-toxic, pharmaceutically acceptable acid addition salts.

Among the preferred compounds of formula I_(A) are those wherein B ishydrogen, methyl or ethyl and those wherein D is methyl, ethyl, methoxyor ethoxy.

Specific preferred compounds of the invention are the syn isomer of3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid, the syn isomer of3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid, the syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid, the syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid and the syn isomer of3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxy-imino-acetamido]-ceph-3-eme-4-carboxylicacid and their salts with alkali metals, alkaline earth metals,magnesium, ammonia and non-toxic, pharmaceutically acceptable organicamines and their easily cleavable esters, 1-acetyloxyethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate,1-acetyloxyethyl3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-ceph-3-eme-4-carboxylicacid and 1-acetyloxyethyl3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

The compounds of formula I' may exist in the indicated form or in theform of the formula ##STR5##

The novel process of the invention for the preparation of compounds offormula I' comprises either (A) reacting a compound of the formula##STR6## wherein Ra, X' and n have the above definitions and A' isselected from the group consisting of hydrogen and an easily eliminableester group with a syn isomer of a compound of the formula ##STR7## or afunctional derivative of the acid wherein R¹ is selected from the groupconsisting of hydrogen and an amino protective group and R' is selectedfrom the group consisting of hydrogen, a hydroxy protective group, alkylof 1 to 6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms and acyl alkoxycarbonyl of 1 to 18carbon atoms, all the said groups being optionally substituted to obtaina compound of the formula ##STR8## wherein R₁, R', A', Ra, X' and n havethe above definitions or (B) reacting a compound of the formula ##STR9##wherein R₁, R', A' and n have the above definitions with either acompound of the formula Ra-SH wherein Ra has the above definition orwith 2-mercaptopyridine-N-oxide and then with a compound of the formulaRa'OH to obtain the corresponding compound of formula IV and optionallywhen n is 0 and X' is sulfur or oxygen, treating the compound of formulaIV with an oxidation agent to obtain a compound of formula IV wherein nis 1 or 2 and X' is oxygen, sulfur or sulfur in the form of sulfoxide orsulfone and if desired, the compounds of formula IV may be subjected toone or more of the following reactions in any order (a) cleaving theester groups or the amino protective groups or the hydroxyl protectivegroups by hydrolysis, hydrogenolysis or reaction with thiourea, (b)esterification or salification with a base of the carboxylic group orgroups (c) salification with an acid of the amino group or groups.

Examples of easily eliminable ester groups of A' are butyl, isobutyl,tert.-butyl, pentyl, hexyl, acetoxymethyl, propionyloxymethyl,butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, 2-acetoxyethyl,2-propionyloxyethyl, 2-butyryloxyethyl, 2-iodoethyl,β,β,β-trichloroethyl, vinyl, allyl, ethynyl, propynyl, benzyl,4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, diphenylmethyl,3,4-dimethoxyphenyl, phenyl, 4-chlorophenyl, tolyl andtert.-butylphenyl.

Examples of amino protective groups of R₁ are alkyl of 1 to 6 carbonatoms, especially tert.-butyl and tert.-amyl and aliphatic, aromatic andheterocyclic acyl groups and a carbamoyl group. Examples of acyl groupsof suitable lower alkanoic acids are formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl. The acylgroups may be substituted with chlorine, bromine, iodine or fluorinesuch as chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl andtrifluoroacetyl, R₁ may also be lower alkoxy carbonyl orcycloalkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, 1-cyclopropyl-ethoxycarbonyl, isopropoxycarbonyl,butyloxycarbonyl, tert.-butyloxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl or acyl of an aryl carboxylic acid such as benzoyl,toluolyl, naphthoyl, phthaloyl, mesyl, phenylacetyl and phenylpropionylor an aralkoxycarbonyl group such as benzyloxycarbonyl.

R₁ may also be araloweralkyl such as benzyl, 4-methoxybenzyl, phenethyl,trityl, 3,4-dimethoxybenzyl or benzhydryl; a haloalkyl such astrichloroethyl; chlorobenzoyl, p-nitrobenzoyl, p-tert.-butylbenzoyl,phenoxyacetyl, caprylyl, n-decanoyl, acryloyl, trichloroethoxycarbonyl,methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl and thecorresponding thio carbamoyl groups. The list is not intended to belimiting and may include other amine protecting groups such as thegroups known in the peptide chemistry.

The hydroxy protecting groups of R' may be acyl of an organic carboxylicacid such as formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,benzoylformyl and p-nitrobenzoyl as well as ethoxycarbonyl,methoxycarbonyl, propoxycarbonyl, β,β,β-trichloroethoxycarbonyl,benzyloxycarbonyl, tert.-butoxycarbonyl, 1-cyclopropylethoxycarbonyl,tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl,trityl, benzyl, 4-methoxy-benzyl, benzyhydryl, trichloroethyl,1-methyl-1-methoxyethyl, phthaloyl; acyls such as propionyl, butyryl,isobutylryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl,phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, p-nitrobenzoyl,p-tert.-butylbenzoyl, caprylyl, acryloyl, methylcarbamoyl,phenylcarbamoyl and naphthylcarbamoyl.

In the preferred mode of the process of the invention, the compound offormula II is reacted with a functional derivative of the acid offormula III such as the acid halide, symetric or mixed acid anhydride,amine, azide or active ester. Examples of mixed acid anhydride is thatformed with isobutyl chloroformate or with pivaloyl chloride and mixedcarboxylic acid-sulfonic acid anhydrides such as formed with p-toluenesulfonyl chloride. The anhydride may be formed in situ by reaction withan N,N-disubstituted carbodiimide such as N,N-dicyclohexylcarbodiimide.Example of an active ester is that formed with 2,4-dinitrophenol orhydroxybenzothiazole and the acid halide may be the acid chloride oracid bromide, for example.

The acylation reaction is preferably effected in an organic solvent suchas methylene chloride but other solvents such as tetrahydrofuran,chloroform or dimethylformamide may also be used. When the acid halideis used and generally when a molecule of hydrogen halide is freed duringthe reaction, the reaction is preferably effected in the presence of abase such as sodium hydroxide, potassium hydroxide, sodium acetate,triethylamine, pyridine, morpholine or N-methyl-morpholine. Theacylation is usually effected at temperatures equal to or less than roomtemperature and the preferred mixed anhydride is a carboxylicacid-sulfonic acid anhydride.

The reaction of a compound of the formula Ra'SH with a compound offormula V is preferably effected under the conditions of French PatentNo. 2,379,540 operating in the presence of the etherate of borontrifluoride in acetic acid or nitro-methane.

The reaction of the compound of formula V with 2-mercapto-pyridineN-oxide and then the RaOH alcohol is preferably effected under theconditions of French Patent No. 2,119,074. The ether formation ispreferably effected in the presence of a copper salt such as cupricchloride.

The oxidation of the compounds of formula IV is preferably effected witha peracid such as peracetic acid, perphthalic acid, m-chloroperbenzoicacid or perbenzoic acid or hydrogen peroxide.

Depending on the values of R₁, R' and A', the compounds of formula IVmay or may not fall within the scope of formula I. When R₁ is hydrogen,R' is not a hydroxyl protective group which can be eliminated and A' isnot easily cleavable ester group, the compounds of formula IV fallwithin the scope of formula I. In the other cases, the compounds offormula IV may be reacted with one or more of hydrolysis agents,hydrogenolysis agents or thiourea to eliminate R₁ when it is an aminoprotective group, to remove R' when it is different from R and/or toeliminate A' when it is an easily cleavable ester group.

However, it is also possible to eliminate the R₁ group without touchingthe R' and A' substitutents when these are desired to be conserved forexample when A' is an ester group which is desired to be conserved suchas propionyloxymethyl. The nature of the reactants put in play in such acase are well known to one skilled in the art and examples of suchreactions are shown in the examples below.

A non-exhaustive enumeration of the ways to eliminate the differentgroups follows. The removal of R₁ may be effected by acidic or basichydrolysis or by the use of hydrazine. Acid hydrolysis is preferred toeliminate optionally substituted alkoxy and cycloalkoxycarbonyl groupssuch as tert.-pentyloxycarbonyl, or tert.-butyloxycarbonyl; optionallysubstituted or alkoxycarbonyl groups such as benzyloxycarbonyl; trityl;benzhydryl; tert.-butyl; or 4-methoxybenzyl. The preferred acids for thehydrolysis are hydrochloric acid, benzene sulfonic acid, p-toluenesulfonic acid, formic acid or trifluoroacetic acid but other mineral ororganic acids may also be used.

The basic hydrolysis is preferably used to remove acyl groups such astrifluoroacetyl and the base is preferably an inorganic base such assodium hydroxide or potassium hydroxide. Equally useful bases aremagnesium hydroxide, baryta or alkali metal carbonates or bicarbonatessuch as sodium carbonate, sodium bicarbonate, potassium carbonate orpotassium bicarbonate or other bases. Also useful are sodium acetate andpotassium acetate. The hydrolysis using hydrazine is preferably used toremove groups such as phthaloyl.

The R₁ group may also be removed with a zinc-acetic acid system forgroups such as trichloroethyl and groups such as benzyhydryl andbenzyloxycarbonyl are preferably removed with hydrogen in the presenceof a catalyst. The chloroacetyl group is preferably removed by action ofthiourea in an acid or neutral media by the reaction described inMasaki, J.A.C.S., Vol. 90 (1968), p. 4508. Other methods known in theliterature for the removal of protective groups are equally useful.

Among the preferred groups are formyl, acetyl, ethoxycarbonyl, mesyl,trifluoroacetyl, chloroacetyl and trityl and the preferred acid used istrifluoroacetic acid.

The removal of A' or R' groups, when it is necessary, is realized undersimilar conditions for those for the removal of R₁ groups. Among others,one may use acid hydrolysis to remove optionally substituted alkyl oraralkyl groups and the acid is preferably selected for the groupconsisting of hydrochloric acid, formic acid, trifluoroacetic acid andp-toluene sulfonic acid. The other groups of A' or R' may, when desired,be removed by procedures known to one skilled in the art, preferablyunder moderate conditions such as at room temperature or slight heating.

Naturally when for example R₁ and A' or R' are removable by differenttypes of reactions, the compounds of formula IV can be subjected todifferent agents of the types discussed above.

The salification of the products is effected by the usual methods. Forexample, a product in the form of an acid or a solvate such as inethanol solvate or an acid hydrate is reacted with a mineral base suchas sodium hydroxide, potassium hydroxide, sodium carbonate, sodiumbicarbonate, potassium carbonate or potassium bicarbonate. Equallyuseful are salts of mineral acids such as trisodium phosphate and saltsof organic acids.

Examples of salts of organic acids are the sodium salts of optionallyunsaturated aliphatic carboxylic acids of 1 to 18 carbon atoms,preferably 2 to 10 carbon atoms. The aliphatic chain may be interruptedwith one or more heteroatoms such as oxygen or sulfur or substitutedwith aryl such as phenyl, thienyl or furyl or with one or more hydroxyor one or more halogens such as fluorine, chlorine or bromine andpreferably chlorine or one more carboxylic or lower alkoxycarbonylgroup, preferably methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl orone or more aryloxy such as phenoxy. When organic acids are used,sufficiently soluble aromatic acids such as substituted benzoic acid,preferably with lower alkyl substitutents, are preferably used.

Examples of specific organic acids whose sodium salts are used areformic acid, acetic acid, acrylic acid, butyric acid, adipic acid,isobutyric acid, n-caproic acid, isocaproic acid, chloropropionic acid,crotonic acid, phenylacetic acid, 2-thienylacetic acid, 3-thienylaceticacid, 4-ethylphenylacetic, glutaric acid, monoethyl adipate, hexanoicacids, heptanoic acids, decanoic acids, oleic acid, stearic acid,palmitic acid, 3-hydroxy-propionic acid, 3-methoxy-propionic acid,3-methylthio-butyric acid, 4-chloro-butyric acid, 4-phenyl-butyric acid,3-phenoxy-butyric acid, 4-ethyl-benzoic acid and 1-propyl-benzoic acid.The preferred sodium salts are sodium acetate, sodium 2-ethylhexanoateand sodium diethylacetate.

The salification may also be effected with an organic base such astriethylamine, diethylamine, trimethylamine, propylamine,N,N-dimethylethanolamine, tris-(hydroxymethyl)-aminomethane,methylamine, ethanolamine, pyridine, picoline, dicyclohexylamine,morpholine and benzylamine. Also useful for the salification arearginine, lysine, procaine, histidine and N-methyl-glucamine.

The salification is preferably effected in a solvent or a mixture ofsolvents such as water, ether, methanol, ethanol or acetone. The saltsmay be crystalline or amorphous depending upon the reaction conditions.Crystalline salts are preferably obtained by reacting the free acid witha salt of an aliphatic carboxylic acid, preferably sodium acetate. Thesalification with organic or mineral acids may be effected under theusual conditions.

The eventual esterification of the products may be effected underclassical conditions, generally reacting an acid of formula I or afunctional derivative thereof with a compound of formula Z-Re wherein Zis --OH or a halogen such as chlorine, bromine or iodine and Re is theester group to be introduced which has been non-exhaustively discussed.In certain cases, it is advantageous to effect esterification with aproduct containing an amino and/or oxyimino group optionally blockedwith a protective group for the amine and oxyimino group.

In a preferred mode of the prcess of the invention for the preparationof compounds of formula I', a compound of formula III wherein R₁ is aprotective amino group in the form of a mixed anhydride with a sulfonicacid is used. Preferably, the sulfonic acid group is p-toluene sulfonicacid and R₁ is trityl.

In another mode of a process for the preparation of a compound offormula I', a compound of the formula ##STR10## wherein Ra, A' and n andX' have the above definitions is reacted with the syn isomer of acompound of the formula ##STR11## or a functional derivative of the acidwherein R₁ " is an amine protective group to obtain a compound of theformula ##STR12## in which A', R"₁, Ra, X' and a have the above meaning,which product of formula (IV') is treated with an acid under moderateconditions, to obtain a product of formula (VI): ##STR13## which may, ifdesired, be esterified or salified and reacting the latter in thepresence of a base with a compound of the formula

    Rd-Hal

wherein Hal is a halogen and Rd is selected from the group consisting ofalkyl of 1 to 6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms, acyl and alkoxycarbonyl, alloptionally substituted to obtain a compound of the formula ##STR14## andsubjecting the compounds of formulae VI or VII to hydrolysis,hydrogenolysis or action of thiourea to remove R₁ " and, if desired, ornecessary, subjecting the product to one or more of the followingreactions in any order (a) removal of ester group or groups, (b)esterification or salification with a base the carboxyl group or groupsand (c) salification of the amino group or groups with an acid.

The R₁ " protective amino group may be any one of the R₁ groupsdiscussed above and the functional derivatives of the acid of formulaIII' may be those discussed for the compounds of formula III. The acidused to treat the compound of formula IV' is preferably aqueoushydrochloric acid. The base used with Rd-Hal is preferably triethylamineor pyridine. The treatment of the compounds of formulae VI and VII iseffected under the conditions described for the compounds of formula IV.

The antibiotic compositions of the invention are comprised of anantibiotically effect amount of at least one compound of formula I' andtheir non-toxic, pharmaceutically acceptable acid addition salts and aninert pharmaceutical carrier. The compositions may be in the form oftablets, dragees, gelules, granules, suppositories, injectable solutionsor suspensions, creams, pomades, gels, etc. prepared in the usualfashion.

Examples of suitable excipients or pharmaceutical carriers are talc,arabic gum, lactose, starch, magnesium stearate, cacao butter, aqueousor non-aqueous vehicles, fatty bodies of vegetable or animal origin,paraffinic derivatives, glycols, preservatives, diverse wetting agents,dispersants and emulsifiers. These compositions can, especially, bepresented in the form of a powder intended to be dissolvedextemporaneously in an appropriate vehicle, for example apyrogeneticsterile water. The compositions on the invention possess very goodantibiotic activity against gram positive bacteria such asstaphylocoecus, streptococcus, particularly penicillin resistantstaphylococcus as well as against gram negative bacteria such ascolliform bacteria. Klebsiella Salmonella, Proteus and Pseudomonas.

The compositions are therefore useful in the treatment of germ sensitiveinfections and particularly those of staphylococcia such asstaphylococcal septicemia, staphylococcia malignant on the face or skin,pyodermatitis, septic or suppurantes sores, anthrax, phlegomons,eresipels, acute primitive or post-grip staphylococcia, bronchopneumoniaor pulmonary suppurations. They are equally useful for the treatment ofcollibacillosis and associated infections, infections of Proteus,Klebsiella, Salmonella, Pseudomonas and other infections caused by gramnegative bacteria. The compositions are also useful to disinfectsurgical instruments.

Among the preferred compositions of the invention are those of formula 1wherein R is hydrogen or alkyl of 1 to carbon atoms optionallysubstituted with free, esterified. or salified carboxyl or --NH₂, thosewherein R_(a) is alkyl of 1 to 6 carbon atoms, especially methyl, thosewherein n is 0 and their non-toxic, pharmaceutically acceptable acidaddition salts.

Also prefered compositions are those containing the syn isomers ofcompounds of the formula ##STR15## wherein R, n, X and Ra have the abovedefinitions, B is selected from the group consisting of hydrogen andoptionally substituted alkyl or 1 to 5 carbon atoms and D is selectedfrom the group consisting of optionally substituted alkyl and alkoxy of1 to 15 carbon atoms, especially 1 to 5 carbon atoms and theirnon-toxic, pharmaceutically acceptable acid addition salts.

Among the preferred compounds of formula I_(A) are those wherein B ishydrogen, methyl or ethyl and those wherein D is methyl, ethyl, methoxyand ethoxy.

The most preferred antibiotic compositions of the invention are thosewherein the active compound is selected from the group consisting of thesyn isomers of 3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid, the syn isomer of3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimine-acetamide]-ceph-3-eme-4-carboxylicacid, the syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid, the syn isomer of3-methylthiomethyl-7-[2(2-amino-4-thiazolyl)-2-methoxyimino-acetamide]-ceph-3-eme-4-carboxylicacid and the syn isomer of3-ethoxymethyl-7[2(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid and their salts with alkali metals, alkaline earth metals,magnesium, ammonia and non-toxic, pharmaceutically acceptable organicamines and their easily cleavable esters, 1-acetyloxyethyl3-methylthiomethyl-7-[2(2-amino-4-thiazolyl)-2-hydroxyiminoacetamide]-ceph-3-eme-4-carboxylate,1-acetyloxyethyl3-methoxymethyl-7-[2(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate and 1-acetyloxyethyl3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

The novel method of the invention of combating bacterial infectious inwarm-blooded animals, including humans comprises administering towarm-blooded animals an antibacterially effective amount of at least onecompound of formula I' and their non-toxic, pharmaceutically acceptableacid addition salts. The compounds may be administered orally, rectally,parenterally, especially intramuscularly, and applied topically to theskin or mucous. The compounds of formula (I_(A)), more particularly theesters of 1-methoxycarbonyloxyethyl or 1-acetyloxyethyl may especiallybe administered orally. The daily active dose will depend upon thecompound used, the condition being treated and the method ofadministration but the usual daily dose when administered orally is 5 to80 mg/kg or when administered intramuscularly is 10 to 20 mg/kg in threetimes.

The novel intermediate products of the invention are the syn isomers ofcompounds of the formula ##STR16## wherein X', Ra, n and A have theabove definitions and either R₁ ' is a amino protective group and R" hasthe definition of R' or R₁ ' is hydrogen and R" is a hydroxyl protectivegroup. Particularly preferred are the compounds of formula IV' and VI.

In addition to the compounds exemplified in the following workingexamples, examples of suitable compounds of formula I' are illustratedin the following Table which indicates the values of n, X', Ra, A and R

                                      TABLE                                       __________________________________________________________________________    n X'                                                                              R'a       A               R                                               __________________________________________________________________________    0 O CH.sub.3  H               CH.sub.2CH.sub.3                                0 O CH.sub.3  H               CH(CH.sub.3).sub.2                              0 O CH.sub.3  H               CHCH.sub.2                                      0 O CH.sub.3                                                                                 ##STR17##      CH.sub.2CH.sub.3                                0 O CH.sub.3                                                                                 ##STR18##      CH(CH.sub.3).sub.2                              0 O CH.sub.3                                                                                 ##STR19##      CHCH.sub.2                                      0 O CH.sub.3                                                                                 ##STR20##      CH.sub.3                                        0 O CH.sub.3  H                                                                                              ##STR21##                                      0 O CH.sub.3                                                                                 ##STR22##      CH.sub.3                                        0 O CH.sub.3                                                                                 ##STR23##       CHCH.sub.2                                     0 O CH.sub.3  H               CH.sub.2CO.sub.2 H                              0 O CH.sub.3  H               C(CH.sub.3).sub.2 CO.sub.2 H                    0 O CH.sub.3  H               (CH.sub.2).sub.2 NH.sub.2                       0 O CH.sub.3  H                                                                                              ##STR24##                                      0 O CH.sub.3  H               COCH.sub.3                                      0 O CH.sub.3  H               CO.sub.2 CH.sub.2 CH.sub.3                      0 O CH.sub.3  H               CON(CH.sub.3).sub.2                             0 O CH.sub.2CH.sub.3                                                                        H               CH.sub.2CO.sub.2 H                              0 O CH.sub.2CH.sub.3                                                                        H               C(CH.sub.3).sub.2CO.sub.2 H                     0 O CH.sub.2CH.sub.3                                                                        H               (CH.sub.2).sub.2 NH.sub.2                       0 O CH.sub.2CH.sub.3                                                                         ##STR25##      H                                               0 O CH.sub.2CH.sub.3                                                                         ##STR26##      CH.sub.3                                        0 O CH.sub.2CH.sub.3                                                                         ##STR27##      H                                               0 O  CH.sub.2CH.sub.3                                                                        ##STR28##      CH.sub.3                                        0 O CH.sub.2CH.sub.3                                                                         ##STR29##      H                                               0 O CH.sub.2CH.sub.3                                                                         ##STR30##      CH.sub.3                                        0 S CH.sub.3  H               CH.sub.2 CH.sub.3                               0 S CH.sub.3  H               CH.sub.2CH.sub.3                                0 S CH.sub.3  H               CH(CH.sub.3).sub.2                              0 S CH.sub.3                                                                                 ##STR31##      CH.sub.2CH.sub.3                                0 S CH.sub.3                                                                                 ##STR32##      CH(CH.sub.3).sub.2                              0 S CH.sub.3                                                                                 ##STR33##      CHCH.sub.2                                      0 S CH.sub.3                                                                                 ##STR34##      CH.sub.3                                        0 S CH.sub.3                                                                                 ##STR35##      CH.sub.3                                        0 S CH.sub.3                                                                                 ##STR36##      CHCH.sub.2                                      0 S CH.sub.3  H               C(CH.sub.3).sub.2 CO.sub.2 H                    0 S CH.sub.3  H               (CH.sub.2).sub.2 NH.sub.2                       0 S CH.sub.3  H                                                                                              ##STR37##                                      0 S CH.sub.3  H               COCH.sub.3                                      0 S CH.sub.3  H               CON(CH.sub.3).sub.2                             0 S CH.sub.2 CH.sub.3                                                                       H               CH.sub.3                                        0 S CH.sub.3CH.sub.3                                                                        H               CH.sub.2CO.sub.2 H                              0 S CH.sub.2CH.sub.3                                                                        H               C(CH.sub.3).sub.2 CO.sub.2 H                    0 S CH.sub.2CH.sub.3                                                                        H               (CH.sub.2).sub.2 NH.sub.2                       0 S CH.sub.2CH.sub.3                                                                         ##STR38##      H                                               0 S CH.sub.2CH.sub.3                                                                         ##STR39##      CH.sub. 3                                       0 S CH.sub.3  H                                                                                              ##STR40##                                      0 S CH.sub.3                                                                                 ##STR41##      H                                               0 S CH.sub.2CH.sub.3                                                                         ##STR42##      H                                               0 S CH.sub.2CH.sub.3                                                                         ##STR43##      CH.sub.3                                        0 S CH.sub.2CH.sub.3                                                                         ##STR44##      H                                               0 S CH.sub.2CH.sub.3                                                                         ##STR45##      CH.sub.3                                        0 O CH(CH.sub.3).sub.2                                                                      H               H                                               1 O CH.sub.3  H               H                                               1 O CH.sub.3  H               CH.sub.3                                        0 O CH.sub.3  H                                                                                              ##STR46##                                      0 O CH.sub.3  H                                                                                              ##STR47##                                      0 O (CH.sub.2).sub.2 CH.sub.3                                                               H               H                                               0 O CH.sub.2CHCH.sub.2                                                                      H               H                                               0 O                                                                                ##STR48##                                                                              H               H                                               0 S CH(CH.sub.3).sub.2                                                                      H               H                                               0 S CH(CH.sub.3).sub.2                                                                      H               CH.sub.3                                        1 S CH.sub.3  H               H                                               1 S CH.sub.3  H               CH.sub.3                                        0 S CH.sub.3  H                                                                                              ##STR49##                                      0 S CH.sub.3  H                                                                                              ##STR50##                                      0 S (CH.sub.2).sub.2 CH.sub.3                                                               H               H                                               0 S (CH.sub.2).sub.2 CH.sub.3                                                               H               CH.sub.3                                        0 S CH.sub.2CHCH.sub.2                                                                      H               CH.sub.3                                        0 S                                                                                ##STR51##                                                                              H               CH.sub.3                                        0 S CH.sub.2CHCH.sub.2                                                                      H               H                                               0 S                                                                                ##STR52##                                                                              H               H                                               __________________________________________________________________________

The starting compounds of formula II are known or can be made by theprocesses described in French Patent Nos. 2,379,540 and 2,119,074. Thecompounds of formulae III and V are described, for example, in FrenchPatent Nos. 2,346,014 and 2,385,722.

In the following examples there are several preferred embodiments toillustrate the invention but it should be understood that the inventionis not intended to be limited to the specific embodiments.

EXAMPLE 13-methoxymethyl-7[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-ceph-3-eme-4-carboxylicacid STEP A: Mixed anhydride of p-toluene sulfonic acid and the synisomer of2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy)-ethoxyimino-aceticacid

1.05 g of tosyl chloride was added to a suspension or 3.01 g of thetriethylamine salt of the syn isomer of2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy)-ethoxyiminoaceticacid in 15 ml of acetone and the mixture was stirred for 90 minutes. 20ml of ether were added to the mixture which was cooled to -10° C. andvacuum filtered. The product was washed with ether to obtain 2.90 g ofmixed anhydride of p-toluene sulfonic acid and the syn isomer of2-(2-tritylamino -4-thiazolyl)-2-(1-methyl-1-methoxy)-ethoxyimino-aceticacid and triethylamine hydrochloride.

STEP B: Syn isomer of 3-methoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid

2.4 g of the mixture of Step A were added to a solution of 0.732 g of3-methoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid, 0.84 g oftriethylamine and 10 ml of methylene chloride cooled to -20° C. and thetemperature was allowed to rise to room temperature. 0.5 ml of aceticacid was added to the mixture which was then washed with water, driedand evaporated to dryness. The residue was triturated with ether and wasvacuum filtered to obtain 3.07 g of product which was crystallized frommethanol to obtain 1.21 g of syn isomer of3-methoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylic acid.

NMR Spectrum (deuterochloroform):

Peaks at 1.52 ppm (hydrogens of geminal methyls); at 3.22-3.25 ppm(hydrogens of methoxy); at 3.45 pp. (hydrogens of methylthio); at 4.25ppm (hydrogens of CH₂ --OCH₃) at 4.99 ppm (d; J=5) (6-hydrogen); at 5.73ppm (dd; J=5 J=8) (7-hydrogen); at 6.70 ppm (5-hydrogen of synthiazole); at 7.28 ppm (trityl)

STEP C: Syn isomer of 3-methoxymethyl-7-[2(2-amino-4-thiazolyl)-2-hydroximino-acetamido]-ceph-3-eme-4-carboxylic acid

A mixture of 1.1 g of the product of Step B and 5 ml of aqueous formicacid was stirred at 45°-50° C. for 10 minutes and 2 ml of water wereadded thereto. The mixture was vacuum filtered and the filtrate wasevaporated to dryness under reduced pressure at 30° C. while entrainingthe water with ethanol. The residue was crystallized from water and wasvacuum filtered to obtain 0.54 g of raw product. The latter wasdissolved in 5 ml of 50% aqueous ethanol containing trietylamie and themixture was adjusted to a pH of 2 to 3 with formic acid. The mixture wasvacuum filtered and the product was washed with ethanol and then withether to obtain 0.44 g of solvated syn isomer of3-methoxymethyl-7-[2(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

Analysis: C₁₄ H₁₅ O₆ N₅ S₂. 0.5H₂ O; molecular weight=422.43;

Calculated: % C 39.9; % H 3.82; % N 16.58; % S 15.18;

Found: % C 40.0; % H 4.0; % N 16.1; % S 14.8.

IR Spectrum (Nujol):

Absorption at 1757 cm⁻¹ (carbonyl of β-lactam); at 1637-1638 cm⁻¹ (C═C,C═N); at 1605-1572-1488 cm⁻¹ (aromatic).

UV Spectrum (ethanol-0.1N HCl): inflex. towards 220 nm E_(1cm) ^(1%)=288. Max. at 262 nm E_(1cm) ^(1%) =421; ε=17,400.

NMR Spectrum (DMSO):

Peaks at 3.20 ppm (hydrogens of methoxy); at 3.50 ppm (hydrogens of SCH₂--); at 4.17 ppm (hydrogens of --CH₂ O--); at 5.14 ppm (d; J=56-hydrogen); at 5.77 ppm (dd; J=5; J=8 7-hydrogen); at 6.65 ppm(5-hydrogen of thiazole); at 7.1 ppm (NH₂); at 9.43 ppm (d; J=8 hydrogenof --NHCO).

EXAMPLE 2 Syn isomer of 1-oxo-propoxymethyl3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: Syn isomer of 1-oxo-propoxymethyl3-methoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 1.71 g of sodium iodide and 23 ml of anhydrous acetone wasrefluxed for 10 minutes to obtain a suspension of iodomethyl propionatewhich was immediately added at 0° C. over 10 minutes to a solution of4.15 g of the syn isomer of3-methoxymethyl-7-[2(2-tritylamino-4-thiazolyl)-2-{(1-methoxy-1-methyl)-ethoxyimino}-acetamido]-ceph-3-4-carboxylicacid, 0.456 g of dry potassium carbonate and 14 ml of anhydrousdimethylformamide and the suspension was stirred at 0° C. for 30minutes, at 20° C. for 30 minutes and was then poured into a mixture of340 ml of water, 17 ml of aqueous sodium bicarbonate solution and 50 mlof ethyl acetate. The mixture was stirred and extracted with ethylacetate. The organic phase was washed with water, dried and evaporatedto dryness under reduced pressure at less than 35° C. The residue wastaken up in 25 ml of isopropyl ether and the mixture was vacuum filteredto obtain 4.42 g of syn isomer of 1-oxo-propoxymethyl3-methoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

NMR Spectrum (deuterochloroform):

Peaks at 1.15 ppm (t, J=7) and at 2.40 ppm (q, J=7) (ethyl); at 3.34 ppm(hydrogens of methoxy); at 3.55 ppm (hydrogens of --SCH₂ --); at 4.33ppm (hydrogens of --CH₂ --OCH₃); at 5.05 ppm (d J=5 6-hydrogen); at 6.71ppm (5-hydrogen of syn thiazole); at 7.33 ppm (trityl).

STEP B: Syn isomer of 1-oxopropoxymethyl3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 4.37 g of the product of Step A in 22 ml of 65% aqueousformic acid was stirred at 45° to 50° C. for 15 minutes and was dilutedwith 90 ml of hot water. The mixture was vacuum filtered and thefiltrate was evaporated to dryness under reduced pressure at less than30° C. The residue was taken up in 100 ml of methylene chloride and theorganic solution was washed with a saturated aqueous sodium chloridesolution diluted to 0.1 and 7 ml of N sodium bicarbonate solution, wasdried and evaporated to dryness under reduced pressure. The residue wastaken up in 100 ml of ether and the mixture was vacuum filtered. The2.10 g of raw product were taken up in 15 ml of ethyl acetate and themixture was stirred for 30 minutes and was vaccum filtered. Therecovered product was rinsed with ethyl acetate and then with ether toobtain 1.69 g of product. 1.57 g of the said product were dissolved in15 ml of methylene chloride and the solution was filtered. The filtratewas evaporated to dryness under reduced pressure and the residue wastaken up in 10 ml of ethyl acetate. The mixture was stirred for 30minutes and was vacuum filtered. The recovered product was rinsed withethyl acetate and with ether to obtain 1.29 g of syn isomer of1-oxopropoxymethyl3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatewith a specific rotation of [α]_(D) ²⁰ =+52°±1° (c=1.5% in DMSO).

NMR Spectrum (deuterochloroform):

Peaks at 1.13 ppm (t: J=7) and at 2.41 ppm (q: J=7) (ethyl); at 3.30 ppm(hydrogens of methoxy); at 3.53 ppm (hydrogens of --SCH₂ --); at 4.3 ppm(hydrogens of --CH₂ --OCH₃); at 5.02 ppm (d: J=5 6-hydrogen); at 6.92ppm (5-hydrogen of syn thiazole).

EXAMPLE 3 Syn isomer of3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamideo]-ceph-3-eme-4-carboxylicacid STEP A: Mixed anhydride of p-toluene sulfonic acid and syn isomerof 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid

A mixture of 1.80 g of the triethylamine salt of the syn isomer of2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetic acid, 0.63 g of tosylchloride and 20 ml of anhydrous acetone was stirred at 20° C. for onehour to obtain a suspension containing mixed anhydride of p-toluenesulfonic acid and syn isomer of2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid what was usedas is for the next step.

STEP B: Syn isomer of 3-methoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid

A solution of 0.732 g of 3-methoxymethyl-7-aminoceph-3-eme-4-carboxylicacid, 6.6 ml of 1N sodium bicarbonate solution and 3.4 ml of water wasformed at 20° C. under an inert atmosphere and the suspension of Step Awas added thereto at 5° C. over 5 minutes. The mixture was stirred at 0°to 5° C. for one hour and at 20° C. for one hour and was then filtered.The acetone was distilled under reduced pressure at not more than 30° C.and the mixture was acidified by addition of 0.7 ml of formic acid. Themixture was extracted with methylene chloride and the organic phase waswashed with water, dried and evaporated to dryness under reducedpressure. The residue was taken up in 10 ml of ether and the mixture wasvacuum filtered to obtain 1.75 g of syn isomer of3-methoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid which was used as is for the next step.

STEP C: Syn isomer of 3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4carboxlic acid

A mixture of 1.07 g of the product of Step B and 8.4 ml of 66% aqueousformic acid was stirred at 45° to 50° C. under an inert atmosphere for12 minutes and then 3.4 ml of water were added at 45° to 50° C. and themixture was vacuum filtered. The filtrate was evaporated to drynessunder reduced pressure while entraining the water with ethanol and theresidue was triturated with 10 ml of water. The mixture was vacuumfiltered and the recovered product was rinsed with water, then withether to obtain 0.436 g of product. Another 0.111 g of product wasobtained from the mother liquors after purification for a total yield of0.547 g. 0.542 g of the said product were taken up in 5.5 ml of waterover one hour and the mixture was vacuum filtered. The product wasrinsed with water and then with ether to obtain 0.453 g of product whichwas empasted with acetone. The mixture was vacuum filtered and theproduct was dried to obtain 0.379 g which was taken up in 10 ml ofwater, 0.83 ml of a 1 M sodium bicarbonate solution were slowly added tothe mixture which was then diluted with 1 ml of 2M sodium chloridesolution. The mixture was vacuum filtered and the filter was rinsed withwater. The filtrate was acidified to a pH ≃3 by addition of 0.5 ml of 2N hydrochloric acid and was vacuum filtered. The recovered product wasrinsed with water, with ether and was empasted with acetone to obtain0.227 g of syn isomer of3-methoxymethyl-7-[2(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

Analysis: C₁₅ H₁₇ O₄ N₅ S₂ : molecular weight=427.459:

Calculated: % C 42.15; % H 4.01; % N 16.38; % S 15.00;

Found: % C 42; % H 3.9; % N 15.8; % S 15.2.

IR Spectrum (Nujol):

Absorption at 1756 cm⁻¹ (β-lactam carbonyl); at 1660 cm⁻¹ (amide); at1637, 1623 and 1562 cm⁻¹ (C═C, C═N conjugated+amide II COO-); at 1031cm⁻¹ (C═NOR).

UV Spectrum (0.1N HCl in ethanol): Inflex. towards 244 nm E₁ ¹ =355;Max. at 262 nm E₁ ¹ =437; ε=18.700

NMR Spectrum (DMSO):

Peaks at 3.22 ppm (hydrogens of methoxy); at 3.85 ppm (N--O--CH₃); at3.53 ppm (hydrogens of --CH₂ S); at 4.18 ppm (hydrogens of --CH₂--OCH₃); at 5.14 ppm (d; J=5 6-hydrogen); at 5.76 ppm (d,d; J=5, J=87-hydrogen); at 6.76 ppm (5-hydrogen of syn thiazole); at 9.60 ppm (d;J=8 NHCO).

EXAMPLE 4 Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: Syn isomer of 3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid

9.5 g of the mixed anhydride of p-toluene sulfonic acid and the synisomer of2-(2-tritylamino-4-thiazolyl)-2-[(1-methyl-1-methoxy)-ethoxyimino]-aceticacid were added at -20° C. to a mixture of 2.60 g of 3-methylthiomethyl-7-amino-ceph-3-eme-4 -carboxylic acid, 37.5 ml ofmethylene chloride and 2.8 ml of triethylamine and the mixture wasstirred at 0° C. for 2 hours. The mixture was acidified with 1.75 ml ofacetic acid and the organic phase was washed with water, dried andevaporated to dryness under reduced pressure. The residue was taken upin 50 ml of ether and the mixture was vacuum filtered. The product wasrinsed with ether to obtain 8.45 g of raw product which was taken up in45 ml of methanol. The mixture was stirred for 30 minutes andcrystallization was induced. The mixture was vacuum filtered and therecovered product was rinsed with methanol and then with ether to obtain5.2 g of syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylicacid.

NMR Spectrum (deuterochloroform):

Peaks at 1.85 ppm (hydrogens of methylthio); at 5.05 ppm (d; J=56-hydrogen); at 5.70 ppm (d,d; J=5, J=8 7-hydrogen); at 6.71 ppm(5-hydrogen of syn thiazole); at 7.28 ppm (trityl).

STEP B: Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

A mixture of 3.72 g of the product of Step A, and 18.6 and of 66%aqueous formic acid was stirred at 50° C. for 10 minutes and then 7.4 mlof water were added thereto. The mixture was vacuum filtered and thefiltrate was distilled to dryness under reduced pressure at not morethan 30° C. while effecting 2 entrainments with a 2-1 ethanol-watermixture. The residue was taken up in 10 ml of water and the mixture wasvacuum filtered. The product was rinsed with water and then ether toobtain 1.945 g of raw product which was taken up in 136 ml of 50%aqueous ethanol. 0.63 ml of triethylamine were slowly added thereto andthe mixture was vacuum filtered. The filtrate was acidified at a pH of≃3-4 by addition of 0.45 ml of 50% aqueous formic acid and was vacuumfiltered. The product was rinsed with 50% aqueous ethanol, anhydrousethanol and finally ether to obtain 1.392 g of syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-ceph-3-eme-4-carboxylicacid.

IR Spectrum (Nujol):

Absorption at 1772 cm⁻¹ (β-lactam carbonyl); at 1693 cm⁻¹ (amide); at1619 cm⁻¹ (NH₂ formation); at 1595 and 1535 cm⁻¹ (aromatic).

UV Spectrum (0.1N HCl in ethanol): Inflex. towards 220 nm E₁ ¹ =320;Max. at 262 nm E₁ ¹ =444; ε=19.100.

NMR Spectrum (deuterochloroform):

Peaks at 1.98 ppm (hydrogens of CH₃ S--); at 3.58 ppm (hydrogens of--CH₂ S--); at 5.17 ppm (d; J=5 6-hydrogen); at 5.72 ppm (d,d; J=5, J=87-hydrogen); at 6.66 ppm (5-hydrogen of syn thiazole); at 9.43 ppm (d;J=8 NHCO).

EXAMPLE 5 Syn isomer of 1-oxopropoxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: Syn isomer of 1-oxopropoxymethyl 3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 5.2 g of the syn isomer of Step A of Example 4, 0.56 g ofpotassium carbonate and 20 ml of anhydrous dimethylformamide was stirredat 20° C. and after cooling to 5° C., 28 ml of a suspension ofiodomethyl propionate in acetone prepared from 1.715 g of chloromethylpropionate were added thereto at 5° to 10° C. The mixture was stirredfor 30 minutes at 5° and at 20° C. for 30 minutes and was then pouredwith stirring into a solution of 260 ml of water, 50 ml of ethyl acetateand 20 ml of aqueous N sodium bicarbonate solution at 10° to 15° C. Theaqueous phase was extracted with ethyl acetate and the organic extractphase was washed with water, dried and evaporated to dryness underreduced pressure. The residue was taken up in 50 ml of isopropyl etherand the mixture was vacuum filtered to obtain 5.53 g of syn isomer of1-oxopropoxymethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

STEP B: Syn isomer of 1-oxopropoxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 3.75 g of the product of Step A and 18.7 ml of 66% aqueousformie acid was stirred at 50° C. for 10 minutes and then 7.5 ml ofwater were added thereto. The mixture was vacuum filtered and thefiltrate was evaporated to dryness under reduced pressure at not morethan 30° C. while entraining twice with a 2-1 methanol-water mixture.The residue was taken up in 10 ml of water and the mixture was vacuumfiltered. The product was rinsed with water then with ether to obtain2.17 g of raw product. The latter was chromatographed over silica geland was eluted with a 3-1 ethyl acetate-acetone mixture. The product wastaken up in 10 ml of isopropyl ether and the mixture was vacuum filteredto obtain 1.55 of product. The latter was taken up in 4.5 ml of ethylacetate and the mixture was added to 7.5 ml of ethyl acetate and themixture was vacuum filtered. The product was rinsed with ethyl acetateand then isopropyl ether to obtain 0.536 g of syn isomer of1-oxopropoxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

UV Spectrum (ethanol): Max. at 222 nm E₁ ¹ =384; ε=19,800; Max. at 262nm E₁ ¹ =271; ε=14,8000.

UV Spectrum (0.1N HCl in ethanol): Inflex. towards 218 nm E₁ ¹ =293;Max. at 263 nm E₁ ¹ =382; ε=19,700.

IR Spectrum (Nujol): Absorption at 1779 cm⁻¹ (β-lactam carbonyl); at1738 and 1759 cm⁻¹ (ester+propionate); at 1664 cm⁻¹ (amide); at 1613cm⁻¹ (NH₂ formation); at 1528 cm⁻¹ (thiazole+amide).

NMR Spectrum (deuterochloroform): Peaks at 1.17 ppm and 2.42 ppm (t; J=7q; J=7 ethyl); at 2.1 ppm (CH₃ S--); at 5.11 ppm (d; J=5 6-hydrogen); at5.9 ppm (hydrogens of --COOCH₂ O--); at 7.1 ppm (5-hydrogen ofthiazole).

EXAMPLE 6 Syn isomer of3-methylthiomethyl-7-[2-(2-amino-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: Syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

A mixture of 2.6 g of 3-methylthiomethyl-7-amino-ceph-3-eme-4-carboxylic acid, 26 ml of methylene chloride and 3 ml oftriethylamine was stirred at 20° C. under an inert atmosphere and aftercooling the mixture to -20° C., an acetone suspension of the mixedanhydride of Example 3 prepared from 6 g of the triethylamine salt ofthe syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-aceticacid was added thereto. The mixture was stirred for 2 hours at 0° C. andwas then acidified with 1 ml of acetic acid. The mixture was evaporatedto dryness under reduced pressure and the residue was taken up in 50 mlof methylene chloride. The organic solution was washed with water, driedand evaporated to dryness under reduced pressure. The residue was takenup in 50 ml of ether and the mixture was vacuum filtered to obtain 8.06g of syn isomer of 3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

STEP B: Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

A mixture of 6.15 g of the product of Step A and 61 ml oftrifluoroacetic acid was stirred at 20° C. for 20 minutes and themixture was evaporated under reduced pressure at 30° C. to a volume of15 ml. 150 ml of ispropyl ether were added at 10° C. to the mixturewhich was then stirred at 20° C. for 15 minutes and was vacuum filtered.The 3.2 g of raw product were chromatographed over silica gel and wereeluted with aqueous 2M sodium chloride solution containing 4% of 1Msodium bicarbonate solution. The raw product was dissolved in a mixtureof 10 ml of eluant, 1.4 ml of aqueous 1M sodium bicarbonate solution, 1ml of triethylamine and 1 ml of aqueous saturated sodium chloridesolution and the solution was acidified to a pH of 3 by addition of 50%aqueous formic acid. The mixture was vacuum filtered and the product waswashed with water and then with ether to obtain 0.99 g of syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

Analysis: C₁₅ H₁₇ O₅ N₅ S₃ ; molecular weight=443.524; Calculated: %C40.62; %H 3.86; %N 15.79; %S 21.69; Found: %C 40.1; %H 3.8; %N 15.5; %S20.8.

IR Spectrum (Nujol): Absorption at 1770 cm⁻¹ shoulder and 1760 cm⁻¹ max(β-lactam carbonyl); at 1660 cm⁻¹ (amide); at 1628 cm⁻¹ (COO+NH₂formation); at 1545 and 1529 cm⁻¹ (amide II+thiazole).

UV Spectrum (ethanol): Max. at 235 nm E₁ ¹ =389; ε=17,300; Inflex.towards 255 nm E₁ ¹ =343; ε=15,200; Inflex. towards 280 nm E₁ ¹ =236.

UV Spectrum (0.1N HCl in ethanol): Max. at 266 nm E₁ ¹ =427; ε=18,900;Inflex. towards 280 nm E₁ ¹ =364.

RNM Spectrum (DMSO): Peaks at 1.98 ppm (CH₃ S); at 3.62 ppm (CH₂ S); at3.85 (OCH₃); at 5.02 ppm (6-hydrogen); at 5.74 (d,d; J=5, J=87-hydrogen); at 6.78 ppm (5-hydrogen of thiazole); at 9.62 ppm (d; J=8NHCO).

EXAMPLE 7 Syn isomer of3-ethylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: 3-ethylthiomethyl-7-amino-ceph-3-eme-4-carboxylic acid

170 ml of the etherate of boron trifluoride and then 45 ml of ethanediolwere added to a mixture of 54.4 g of 7-amino-cephalosporanic acid and544 ml of acetic acid and the mixture was stirred at 45°-50° C. for 2hours and was then cooled to 20° to 30° C. 170 ml of triethylamine wereadded to the mixture which was then vacuum filtered. The product wasrinsed with acetic acid, with acetone and then with ether to obtain32.45 g of 3-ethylthiomethyl-7-amino-ceph-3-eme-4-carboxylic acid.

UV Spectrum (0.1N HCl-ethanol): Max. at 262 nm E₁ ¹ =217; ε=5,950.

NMR Spectrum (DMSO): Peaks at 1.13 ppm (t; J=7) and 2.46 ppm (q;J=7)(--S--CH₂ --CH₃); at 3.6 ppm (--CH₂ --S--); at 4.72-4.79 ppm and4.98-5.05 ppm (hydrogen of β-lactam).

STEP B: Syn isomer of3-ethylthiomethyl-7-[2-(2-trityl-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

A solution of 1.37 g of the product of Step A, 1.75 ml of triethylamineand 15 ml of methylene chloride at room temperature under an inertatmosphere was cooled to -30° C. and 3.97 g of the mixed anhydride oftosyl and the syn isomer of2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-aceticacid were added thereto all at once. The temperature was allowed to riseto 0° C. and was stirred for 2 hours at 0° C. The mixture wasneutralized by the addition of 0.75 ml of acetic acid and was extractedwith methylene chloride. The organic phase was washed with water, driedand evaporated to dryness under reduced pressure at less than 30° C. Theresidue was triturated with 20 ml of ether and was vacuum filtered toobtain 3.55 g of product which was crystallized from methanol to obtain2.17 g of syn isomer of 3-ethylthiomethyl-7-[2-(2-trityl-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.

STEP C: Syn isomer of3-ethylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamino]-ceph-3-eme-4-carboxylicacid

A solution of 2.16 g of the product of Step B and 10.8 ml of 66% aqueousformic acid was stirred at 50° C. for 10 minutes and 4.3 ml of waterwere added thereto. The mixture was vacuum filtered and the filtrate wasevaporated to dryness under reduced pressure at less than 35° C. Theresidue was taken up in 6 ml of water and was then vacuum filtered. Theproduct was dried to obtain 1.168 g of product which was dissolved in 6ml of water and 0.4 ml of triethylamine. The crystallized triethylaminesalt was added to 10 ml of water and the mixture was filtered. Thefilter was rinsed with 5 ml of methanol and the filtrate was added to 11ml of ethanol. The mixture was acidified to a pH of 3-4 by addition of 1ml of 50% aqueous formic acid and stood for 30 minutes at 20° C. and wasthen vacuum filtered. The product was rinsed with anhydrous ethanol andthen with ether to obtain 0.885 g of syn isomer of3-ethylthiomethyl-7-[2(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 218 nm E₁ ¹ =320; Max.at 263 nm E₁ ¹ =448; ε=19,900.

NMR Spectrum (DMSO): Peaks at 1.15 ppm (t; J=7) and 2.62 ppm (q;J=7)(--S--CH₂ --CH₃); at 3.61 ppm (--CH₃ --CH₂ --S--CH₂ --); at 11.4 ppm(N--OH); at 6.75 ppm (5-hydrogen of thiazole); at 5.12-5.2 ppm(6-hydrogen); at 5.61-5.7 ppm and 5.75-5.83 ppm (7-hydrogen); at9.62-9.48 ppm (NH--C═O).

EXAMPLE 8 Syn isomer of3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: 3-ethoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid

128 ml of the etherate of boron trifluoride and then 71 ml of ethanolwere added with stirring to a mixture of 27.2 g of7-amino-cephalosporanic acid and 272 ml of anhydrous acetonitrile andthe mixture was heated at 45°-50° C. under an inert atmosphere. Themixture was cooled to 15°-20° C. and 98 ml of triethylamine were addedthereto over 15 minutes. The mixture was vacuum filtered and the productwas rinsed with acetonitrile, acetone and then ether to obtain 19.25 gof raw product 18 g of which was dissolved in 54 ml of 2N hydrochloricacid. The solution was heated to 45° C., treated with activated carbonand filtered. The filtrate was neutralized hot by addition of 11 ml ofammonium hydroxide solution and was vacuum filtered at 20° C. Theproduct was rinsed with water, acetone and then ether to obtain 8.6 g ofproduct, 5.86 g of the said product were taken up in 24 ml of 2Nhydrochloric acid and the mixture was stirred at 45° C. for one hour. 4ml of hot ammonium hydroxide were added thereto and the mixture wasvacuum filtered at 20° C. The product was rinsed with water, acetone andthen ether to obtain 4.75 g of3-ethoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid.

UV Spectrum (0.1N HCl-ethanol): Max. at 259 nm E₁ ¹ =239; ε=6,200.

NMR Spectrum (DMSO): Peaks at 1.08 ppm (t: J=7) and at 3.39 ppm (q: J=7)(--OCH₂ --CH₃); at 4.18 ppm (O--CH₂ --); at 4.72-4.8 ppm and 4.93-5.03ppm (6- and 7-hydrogens).

STEP B: Syn isomer of3-ethoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-1-methoxy 1-methylethoxyimino-acetamido]ceph-3-eme-4-carboxylic acid.

Using the procedure of Step B of Example 7, 1.29 g of the product ofStep A was reacted to obtain 3.74 g of raw product which wascrystallized from ethyl acetate to obtain 1.791 g of syn isomer of3-ethoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-]1-methoxy 1-methylethoxyimino acetamdio/-ceph 3-eme-4-carboxylic acid.

UV Spectrum (ethanol): Inflex. towards 230 nm E₁ ¹ =370; Inflex. towards260 nm E₁ ¹ =233; ε=17,300; Inflex. towards 300 nm E₁ ¹ =80; ε=5,900.

UV Spectrum (0.1N HCl-ethanol): Max. at 271 nm E₁ ¹ =256; ε=19,000.

NMR Spectrum (deuterochloroform): Peaks at 1.05-1.13-1.21 ppm and3.23-3.31-3.38-3.47 ppm (--OCH₂ --CH₃); at 1.54 ppm (geminal methyls);at 3.24 ppm (methoxy); at 3.51 ppm (--S--CH₂ --); at 4.15 ppm (--CH₂--O); at 4.98-5.05 ppm (6-hydrogen); at 5.68 to 5.87 ppm (7-hydrogen);at 6.75 ppm (5-hydrogen of thiazole).

STEP C: Syn isomer of3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

A solution of 1.735 g of the product of Step B and 8.6 ml of 66% aqueousformic acid was heated at 50° C. for 10 minutes and 3.5 ml of hot waterwere added thereto. The mixture was vacuum filtered and the filtrate wasevaporated to dryness under reduced pressure. The residue was taken upin 5 ml of 50% aqueous ethanol and the solution was evaporated todryness at less than 35° C. The residue was taken up in 6 ml of waterand was triturated and vacuum filtered. The product was-rinsed withwater and then with ether to obtain 0.915 g of raw product 0.813 g ofwhich was dissolved in 10 ml of 50% aqueous ethanol and 0.45 ml oftriethylamine. The mixture was filtered and the filter was rinsed with 6ml of aqueous ethanol. The filtrate was acidified to a pH of 3.4 byaddition of 0.7 ml of 50% aqueous formic acid and crystallization wasinduced. The mixture was vacuum filtered and the product was rinsed withaqueous ethanol and then with ether to obtain 0.688 g of syn isomer of3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 219 nm E₁ ¹ =288;ε=12,300; Max. at 261 nm E₁ ¹ =409; ε=17,500.

NMR Spectrum (DMSO): Peaks at 1.11 ppm (t: J=7) and at 3.40 ppm (q:J=7)(--OCH₂ --CH₃); at 4.22 ppm (--CH₂ O--); at 5.11-5.19 ppm(6-hydrogen); at 5.67-5.75-5.8-5.87 ppm (7-hydrogen); at 6.75 ppm(5-hydrogen of thiazole); at 7.17 ppm (--NH₂ --); at 9.47-9.6 ppm(NHCO).

EXAMPLE 9 Syn isomer of3-(2-propenyloxymethyl)-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: 3-allyloxymethyl-7-amino-ceph-3-eme-4-carboxylic acid

Using the procedure of Step A of Example 8, 27.2 g of7-amino-cephalosporanic acid, 170 ml of the etherate of borontrifluoride, 136 ml of allyl alcohol and 115 ml of triethylamine werereacted and the 9 g of raw product was purified successively twice withhot hydrochloric acid and ammonium hydroxide to obtain 4.72 g of3-allyloxymethyl-7-amino-ceph-3-eme-4-carboxylic acid.

UV Spectrum (0.1N HCl-ethanol): Max. at 259-260 nm E₁ ¹ =244; ε=6,600.

NMR Spectrum (DMSO): Peaks at 4.23 ppm (--CH₂ O); at 5.62 to 6.25 ppm(hydrogen of --O--CH═CH₂); at 4.72-4.8 ppm and 4.95-5.03 ppm (hydrogenof β-lactam). STEP B: Syn isomer of3-(2-propenyloxymethyl)-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid

0.67 ml of triethylamine was added with stirring at -20° C. to a mixtureof 0.96 g of the sym isomer of2-(2-amino-4-thiazolyl)-2-methoxyimino-acetic acid, 0.912 g of tosylchloride and 4 ml of anhydrous dimethylacetamide and the mixture wasstirred at -20° C. for one hour. A solution cooled to -65° to -70° C.obtained by reacting 0.992 g of the product of Step A, 10 ml ofmethylene chloride and 1.5 ml of triethylamine at 15° to 20° C. wereadded over 5 minutes to the mixture cooled to -20° C. and the mixturewas stirred at -65°±2° C. for 30 minutes 2 ml of a 1--1 aceticacid-methylene chloride were added thereto and the mixture was stirredfor 15 minutes at -65° C. after which the temperature was allowed torise to -50° C. 2 ml of water were added to the mixture and after thetemperature rose to 0° C., 4 ml of 50% aqueous formic acid were addedthereto. The methylene chloride was distilled under reduced pressure atless than 30° C. and 11 ml of water were added thereto followed by theaddition of 50 ml of aqueous saturated sodium chloride solution. Theaqueous phase was decanted and the gummy precipitatic was empasted with5 ml of water. The mixture was vacuum filtered and the product wasrinsed with water and with ether to obtain 0.728 g of raw product. Thevarious aqueous phases were added to 20 ml of aqueous saturated sodiumchloride solution and the mixture was extracted with methyl acetate. Theorganic phase was dried and evaporated to dryness and the residue wastaken up in 20 ml of aqueous saturated sodium chloride solution. Theprecipitate was empasted with 5 ml of water to obtain 0.338 g of rawproduct which was chromatographed over silica gel. Elution with 2Msodium chloride solution containing 4°‰ of 1M sodium bicarbonatesolution yielded 1.060 g of raw product. The aqueous fractions wereacidified to a pH of 3 to 4 with 50% aqueous formic acid and was vacuumfiltered to obtain 0.18 g of syn isomer of3-(2-propenyloxymethyl)-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid. Another 0.368 g of the said product was obtained from the filtrateby extraction with methyl acetate as before.

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =423; ε=19,200.

NMR Spectrum (DMSO): Peaks at 3.84 ppm (N--O--CH₃); at 3.86-3.93 ppm(hydrogens of O--CH₂ --CH═); at 4.24 ppm (--CH₂ O); at 5.13 to 5.33 ppm(═CH₂ and 6-hydrogen); at 5.7 to 6.1 ppm (7-hydrogen and hydrogen of--CH═CH₂); at 6.72 ppm (5-hydrogen of thiazole); at 9.5-9.6 ppm(--NHCO--).

EXAMPLE 10 Syn isomer of3-propoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: 3-propoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid

Using the procedure of Step A of Example 8, 27.2 g of7-amino-cephalosporanic acid, 170 ml of the etherate of of borontrifluoride, 131 ml of propanol and 128 ml of triethylamine were reactedto obtain 17.4 g of raw product which was purified with hot hydrochloricacid and ammonium hydroxide to obtain 7.45 g of3-propoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid.

UV Spectrum (0.1N HCl- ethanol): Max. at 259 nm E₁ ¹ =238; ε=6,500.

NMR Spectrum (DMSO): Peaks at 0.72-0.85-0.97 ppm (CH₃ --); at 1.2 to 1.8ppm (hydrogens of CH₃ --CH₂ --); at 3.2-3.3-3.4 ppm (hydrogens of--O--CH₂ --CH₂ --); at 4.2 ppm (hydrogens of --CH₂ --O--C₃ H₇); at4.7-4.78 ppm and 4.95-5.03 ppm (6- and 7-hydrogens).

STEP B: Syn isomer of2-propoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

A mixture of 1.440 g of the syn isomer of2-(2-amino-4-thiazolyl)-2-methoxyimino-acetic acid, 1.368 g of tosylchloride and 6 ml of anhydrous dimethyacetamide was cooled to -15° to-20° C. under an inert atmosphere and 1 ml of triethylamine was addedover 2 minutes at -15° to -20° C. The mixture was stirred for one hourat -15° to -20° C. and a solution cooled to -65° to -70° C. and obtainedby reacting 1.5 g of the product of Step A, 2.25 ml of triethylamine and15 ml of methylene chloride at 15° to 20° C. was added over 5 minutes tothe mixture at -20° C. The mixture was stirred at -65°±2° C. for 30minutes and then 3 ml of a 1--1 acetic acid-methylene mixture were addedthereto. The mixture was stirred at -65° C. for 15 minutes and after thetemperature rose to -50° C., 3 ml of water were added thereto. AT 0° to5° C., 6 ml of a 50% aqueous formic acid were added thereto and themethylene chloride was distilled under reduced pressure at less than 30°C. while adding 165 ml of water. Then 25 ml of water and 25 ml of anaqueous saturated sodium chloride solution were added to the mixturewhich was then extracted with ethyl acetate. The organic phase waswashed with an aqueous half saturated sodium chloride solution, wastreated with activated carbon, dried and evaporated to dryness underreduced pressure. The residue was taken up in 100 ml of aqueoussaturated sodium chloride solution and the aqueous phase was decanted.The gummy residue was empasted with 5 ml of water to solidify theproduct and the mixture was vacuum filtered. The product was rinsed withwater and then with ether to obtain 1.682 g of raw product. The washwaters were extracted with methyl acetate and the organic phase wasdried and evaporated to dryness. The residue was taken up in 50 ml ofaqueous saturated sodium chloride solution and the mixture was vacuumfiltered to obtain 0.538 g of raw product. The latter was taken up in 20ml of water and the solution was extracted with methyl acetate. Theorganic phase was dried and evaporated to dryness under reducedpressure. The residue was triturated with 5 ml of ether and was vacuumfiltered to obtain 0.450 g of syn isomer of2-propoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

UV Spectrum (ethanol): Max. at 237 nm E₁ ¹ =359; ε16,400; Inflex.towards 251 nm E₁ ¹ =322; ε=14,700; Inflex. towards 290 nm E₁ ¹ =157.

UV Spectrum (0.1N HCl-ethanol): Max. at 263 nm E₁ ¹ =388; ε=17,700.

NMR Spectrum (DMSO): Peaks at 0.85 ppm (t: J=7)(CH₃ -- of propyl); at3.32 ppm (t:J=7)(hydrogens of --OCH₂ --CH₂ --); at 4.23 ppm (--CH₂ O--);at 5.12-5.2 ppm (6-hydrogen); 5.65-5.73 ppm and 5.78-5.87 ppm(7-hydrogen); at 6.81 ppm (5-hydrogen of thiazole); at 3.9 ppm(--N--O--CH₃); at 3.55 ppm (--CH₂ --S--); at 9.58-9.72 ppm (NHCO).

EXAMPLE 11 Syn isomer of3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

Using the procedure of Example 9, 0.949 g of3-ethoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid were reacted up tothe stage of removal of methylene chloride and addition of water. Themixture was added to 60 ml of aqueous saturated sodium chloride solutionand was vacuum filtered. The product was rinsed with water and then withether to obtain 0.250 g of raw product. The wash waters were extractedwith methyl acetate and the organic phase was dried and evaporated todryness. The residue was taken up in 50 ml of aqueous saturated sodiumchloride solution and the mixture was filtered. The product was empastedwith 5 ml of water and was vacuum filtered to obtain 0.361 g of rawproduct.

The first fraction was chromatographed over silica gel and was elutedwith a 2M sodium chloride solution containing 4‰ of 1M sodiumbicarbonate solution. The desired fractions were acidified to a pH of 3to 4 by addition of 50% aqueous formic acid and the organic phase wasdried and evaporated to dryness. The residue was taken up in 5 ml ofether, triturated and vacuum filtered to obtain 0.122 g of product. Thelatter product and the second fraction were taken up in 5 ml of waterand 1.4 ml of 1M sodium bicarbonate solution and the mixture was treatedwith activated carbon and acidified to a pH of 3 to 4 by addition of 0.3ml of 50% aqueous formic acid. The mixture was extracted with methylacetate and the organic extract was dried and evaporated to dryness. Theresidue was taken up in ether and filtered to obtain 0.366 g of synisomer of 3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

UV Spectrum (ethanol): Max. at 235 nm E₁ ¹ =411; ε=18,100; Inflex.towards 251 nm E₁ ¹ =361; ε=15,900; Inflex. towards 290 nm E₁ ¹ =174.

U.V. Spectrum (0.1N HCl in ethanol): Max. at 263-264 nm E₁ ¹ =429;ε=18,900.

NMR Spectrum (DMSO): Peaks at 1.11 ppm (t: J=7) and at 3.28-3.35 ppm and3.37-3.51 ppm (O--CH₂ --CH₃); at 3.83 ppm (NOCH₃); at 3.80 ppm (--OCH₂--); at 5.11-5.17 ppm (6-hydrogen); at 5.68-5.73 ppm and 5.77-5.82 ppm(7-hydrogen); at 6.73 ppm (5-hydrogen of thiazole); at 9.51-9.6 ppm(NHCO). EXAMPLE 12 Syn isomer of3-isopropoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: 3-isopropoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid

Using the procedure of Step A of Example 8, 27.2 g of7-amino-cephalosporanic acid, 170 ml of the etherate of borontrifluoride, 134 ml of isopropanol and 125 ml of triethylamine werereacted to obtain 16.25 g of raw product which was purified by twosuccessive treatments with hot hydrochloric acid and ammonium hydroxideto obtain 5.8 g of 3-isopropoxymethyl-7-amino-ceph-3-eme-4-carboxylicacid.

UV Spectrum (0.1N HCl-ethanol): Max. at 259 nm E₁ ¹ =233; ε=6,300.

NMR Spectrum (DMSO): Peaks at 1.02-1.12 ppm (hydrogens of ##STR53## at4.2 ppm (--CH₂ O--); at 4.7-4.8 ppm and 4.95-5.03 ppm (6- and7-hydrogens).

STEP B: Syn isomer of3-(isopropoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

Using the procedure of Example 9, 1 g of the product of Step A wasreacted to the removal of methylene chloride and addition of water and40 ml of aqueous half-saturated sodium chloride solution were addedthereto. The mixture was extracted with methyl acetate and the organicphase was dried and evaporated to dryness under reduced pressure. Theoily residue was taken up in 50 ml of aqueous saturated sodium chloridesolution and the mixture was triturated and vacuum filtered. The productwas rinsed with water and then ether to obtain 0.602 g of syn isomer of3-(isopropxoymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid. The wash waters were extracted with methyl acetate and the organicphase was dried and evaporated to dryness under reduced pressure. Theresidue was taken up in 50 ml of ether and vacuum filtered to obtain0.686 g of the desired product.

UV Spectrum (ethanol): Max. at 236 nm E₁ ¹ =359; ε=16,400; Inflex.towards 252 nm E₁ ¹ =318; ε=14,500; Inflex. towards 291 nm E₁ ¹ =151.

UV Spectrum (0.1N HCl-ethanol): Max. at 263 nm E₁ ¹ =385; ε=17,500.

NMR Spectrum (DMSO): Peaks at 1.03-1.15 ppm (hydrogens of ##STR54## at˜3.57 ppm (--CH₂ S--); at 4.23 ppm (hydrogens of OCH₂ --); at 3.88 ppm(hydrogens of --N--O--CH₃); at 5.12-5.2 ppm (6-hydrogen); at 5.65-5.73ppm and 5.78-5.87 ppm (7-hydrogen); at 6.82 ppm (5-hydrogen ofthiazole); at ˜9.58-9.72 ppm (--NHCO--).

EXAMPLE 13 Syn isomer of3-benzyloxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: 3-benzyloxy-7-amino-ceph-3-eme-4-carboxylic acid

Using the procedure of Step A of Example 8, 27.2 g of7-amino-cephalosporanic acid, 128 ml of the etherate of borontrifluoride, 126 ml of benzyl alcohol and 90 ml of triethylamine werereacted to obtain 27.1 g of raw product. 25 g of the said product and250 ml of acetic acid were added to 25 ml of the etherate of borontrifluoride followed by the addition of 25 ml of triethylamine whichcaused precipitation. The mixture was vacuum filtered and the productwas rinsed with acetic acid, acetone and then ether to obtain 4.6 ofproduct. 4.8 g of the said product were dissolved at 45° C. in 20 ml of2N hydrochloric acid and 8 ml of concentrated hydrochloric acid and thesolution was treated with activated carbon. 6 ml of ammonium hydroxidewere added to the mixture which was then vacuum filtered. The productwas rinsed with water, acetone and then ether to obtain 2 g of3-benzyloxy-7-amino-ceph-3-eme-4-carboxylic acid.

UV Spectrum (0.1N HCl-ethanol): Max. at 259 nm E₁ ¹ =216; ε=6,900.

NMR Spectrum (DMSO): Peaks at 4.28 and 4.45 ppm (--CH₂ O--CH₂ --); at4.73-4.82 ppm and 4.95-5.03 ppm (6- and 7-hydrogens); at 7.33 ppm(aromatic).

Step B: Syn isomer of3-benzyloxymethyl-7-[2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

Using the procedure of Example 9, 1.175 g of the product of Step A werereacted up to the removal of methylene chloride and addition of water.An aqueous saturated sodium chloride solution was added to the mixturewhich was then vacuumed filtered. The product was rinsed with water andthen with either to obtain 0.905 g and then 0.590 g of product. 0.707 gof the product were dissolved in 7 ml of water and 0.2 ml oftriethylamine and the solution was treated with activated carbon 0.15 mlof 50% aqueous formic acid were added to the mixture which was vacuumfiltered to obtain 0.484 g of product which together with the 0.590 g ofproduct was triturated in 10 ml of 50% aqueous ethanol containing 0.6 mlof formic acid. The mixture stood at 20° C. for 15 minutes and wasvacuumed filtered. 1.6 ml of ammonium hydroxide and 20 ml of water wereadded to the filtrate and the mixture was extracted with methyl acetate.The organic phase was washed with water, dried and evaporated to drynessunder reduced pressure. The residue was triturated with 10 ml of ethanoland the mixture was vacuum filtered. The product was rinsed with ethanoland then with ether to obtain 0.283 g of syn isomer of3-benzyloxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

UV Spectrum (ethanol): Max. at 237 nm E₁ ¹ 350; ε=17,700; Inflex.towards 255 nm E₁ ¹ =308; Inflex. towards 290 nm E₁ ¹ =154;

UV Spectrum (0.1N HCl-ethanol): Max. at 262 nm E₁ ¹ =367; ε=18,500.

NMR Spectrum (DMSO): Peaks at 3.85 ppm (hydrogens of N--OCH₃); at 4.31ppm (hydrogens of --CH₂ O--); at 4.45 ppm (hydrogens of --O--CH₂ φ); at5.12-5.2 ppm (6-hydrogen); at 5.68-5.77 ppm and 5.82-5.9 ppm(7-hydrogen); at 6.75 ppm (5-hydrogen of thiazole); at 7.33 ppm(phenyl); at ˜9.52-9.65 ppm (NHCO).

EXAMPLE 14 Syn isomer of3-(2-methoxyethoxy)-methyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid Step A: 3-(2-methoxyethoxy)-methyl-7-amino-ceph-3-eme-4-carboxylicacid

Using the procedure of Step A of Example 8, 27.2 g of7-amino-cephalosporanic acid, 170 ml of the etherate of borontrifluoride, 136 ml of 3-methoxy-ethanol and 125 ml of triethylaminewere reacted to obtain 19.25 g of raw product. A mixture of 17 g of thesaid product, 170 ml of methylene chloride and 8.3 ml of triethylaminewas stirred for 20 minutes and was vacuumed filtered. The 9.28 g ofdried product were taken up in 130 ml of acetone containing 2% of waterand 4.5 of triethylamine and the mixture was stirred for 15 minutes andwas then filtered. The product was rinsed with acetone and then withether to obtain 6.35 g of product which was treated in the same fashionto obtain 5.77 g of3-(2-methoxyethoxy)-methyl-7-amino-ceph-3-eme-4-carboxylic acid.

UV Spectrum (0.1N HCl-ethanol): Max. at 260-261 nm E₁ ¹ =226; ε=6,500;Inflex. towards 330 nm E₁ ¹ =9.

NMR Spectrum (DMSO): Peaks at 3.23 ppm (OCH₃); at 3.45 ppm (--CH₂ --Sand --O--CH₂ --CH₂ --O--); at 4.23 ppm (--CH₂ O--); at 4.7-4.77 ppm and4.92-5 ppm (6- and 7-hydrogens).

Step B: Syn isomer of3-(2-methoxyethoxy)-methyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

Using the procedure of Example 9, 1.160 g of the product of Step A werereacted up to the methylene chloride removal and water addition and then50 ml of aqueous saturated sodium chloride solution were added. Themixture was vacuum filtered and the filtrate was extracted with methylacetate. The organic phase was washed with water, dried and evaporatedto dryness under reduced pressure and the residue was taken up in 50 mlof aqueous saturated sodium chloride solution. The decanted liquid phasewas extracted with methyl acetate and the organic phase was washed withwater, dried and evaporated to dryness under reduced pressure at lessthan 30° C. The residue was triturated with 20 ml of ether and wasvacuum filtered to obtain 0.725 g of raw product. 0.720 g of the latterwere taken up in 15 ml of water and the mixture was stirred at 20° C.for 5 minutes and was vacuum filtered. The filtrate was extracted withmethyl acetate and the organic phase was washed with water, dried andevaporated to dryness under reduced pressure. The residue was trituratedwith 20 ml of ether and was vacuum filtered to obtain 0.500 g of synisomer of 3-(2-methoxyethoxy)-methyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

UV Spectrum (ethanol): Max. at 238 nm E₁ ¹ =342; ε=16,000; Inflex.towards 250 nm E₁ ¹ =313; Inflex. towards 290 nm E₁ ¹ 141.

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =369; ε=17,400.

NMR Spectrum (DMSO): Peaks at 3.23 ppm (OCH₃); at 3.45 ppm (--OCH₂ --CH₂--O--); at 3.83 ppm (NOCH₃); at 4.28 ppm (--CH₂ O--); at 5.11-5.17 ppm(6-hydrogen); at 5.69-5.74 ppm and 5.77-5.83 ppm (7-hydrogen); at 6.74ppm (5-hydrogen of thiazole); at 7.22 ppm (NH₂); at 9.5-9.6 ppm (NHCO).

EXAMPLE 15 Syn isomer3-methoxymethyl-S-oxido-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid Step A: Syn isomer of3-methoxymethyl-S-oxido-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid

1.45 g of the syn isomer of3-methoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy)-ethoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid were dissolved at room temperature in 14 ml of methylene chlorideand after cooling the mixture to -20° C., 440 mg of m-chloro-perbenzoicacid were added thereto. The mixture was stirred for 15 minutes and thetemperature was allowed to rise to room temperature. 10 ml of isopropylether were added to the mixture and the methylene chloride wasdistilled. Another 10 ml of isopropyl ether were added thereto and themixture was vacuum filtered to obtain 1.47 g of raw syn isomer of3-methoxymethyl-S-oxido-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid.

Step B: Syn isomer of3-methoxymethyl-S-oxido-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

50 ml of ether were added to a mixture of 1.47 g of the product of StepA and 5 ml of a 66% aqueous formic acid solution and the mixture wasvacuum filtered. The 0.785 g of product was taken up in 1 ml of waterand 2 drops of pyridine and 10 ml of ethanol were added to the mixturewhich was vacuumed filtered. The product was rinsed with ethanol andthen with ether to obtain 0.51 g of syn isomer of3-methoxy-methyl-S-oxido-7-[2-(2-amino-4-thiazolyl)-2-hydroximino-acetamido]-ceph-3-eme-4-carboxylicacid.

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 218 nm E₁ ¹ =303; Max.at 261 nm E₁ ¹ =423; ε18,200; Inflex. towards 375 nm E₁ ¹ =2.

NMR Spectrum (DMSO): Peaks at 3.25 ppm (OCH₃); at 4.3-4.5 ppm and 4.4.21ppm (--CH₂ O--); at 4.98-5.06 ppm (6-hydrogen); at 6.83 ppm (5-hydrogenof thiazole); at 5.95-5.98 ppm and 6.05-6.13 ppm (7-hydrogen).

EXAMPLE 16 Syn isomer of3-methylsulfinylmethyl-S-oxido-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

Using the procedure of Example 15, 0.744 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and 0.404 g of m-chloro-perbenzoic acid were reacted to obtain0.250 g of syn isomer of3-methylsulfinylmethyl-S-oxido-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

UV Spectrum (0.1N HCl-ethanol): Max. at 269 nm E₁ ¹ =396; ε=18,300.

NMR Spectrum (DMSO): Peaks at 2.6 ppm (CH₃ --SO); at 5-5.08 ppm(6-hydrogen); at 5.88-5.96 ppm and 6.03-6.12 ppm (7-hydrogen); at 6.78ppm (5-hydrogen of thiazole).

EXAMPLE 17 Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-benzyloxyimino-acetamido]-ceph-3-eme-4-carboxylicacid Step A: Ethyl2-(2-tritylamino-4-thiazolyl)-2-benzyloxyimino-carboxylate

23 ml of benzyl chloride were added over 5 minutes at 0° C. to a mixtureof 9.88 g of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-carboxylate hydrochloride (described in French Patent No.2,383,188), 50 ml of dimethylformamide and 13.8 g of potassium carbonateand the mixture was stirred at room temperature for 20 hours. 500 ml ofwater and 100 ml of ethyl acetate were added to the mixture and thedecanted organic phase was washed with water, dried and evaporated todryness under reduced pressure. The residue was chromatographed oversilica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixtureto obtain 5.51 g of ethyl2-(2-tritylamino-4-thiazolyl)-2-benzyloxyimino-carboxylate.

Step B: Syn isomer of2-(2-tritylamino-4-thiazolyl)-2-benyzloxyimino-acetic acid

A mixture of 5.3 g of the product of Step A, 30 ml of ethanol, 8 ml ofdioxane and 4.8 ml of 2N sodium hydroxide solution was stirred at roomtemperature for 20 hours and was then vacuum filtered. The product wasrinsed with a 4-1 ethanol-dioxane mixture and then with ether to obtain4.452 g of sodium salt. The latter was added to 50 ml of water, 50 ml ofmethylene chloride and 6 ml of 2N hydrochloric acid and the decantedorganic phase was washed with water, dried and evaporated to drynessunder reduced pressure. The residue was taken up in isopropyl ether,vacuum filtered and dried to obtain 3.708 g of2-(2-tritylamino-4-thiazolyl)-2-benzyloxyimino-acetic acid melting at≃153° C.

NMR Spectrum (deuterochloroform): Peaks at 7.3 ppm (φs); at 6.5 ppm(5-hydrogen of thiazole); at 5.25 ppm (CH₂ --φ).

Step C.: Mixed anhydride of p-toluene sulfonic acid and the syn isomerof 2-(2-tritylamino-4-thiazolyl)-2-benzyloxyimino-acetic acid

0.95 g of tosyl chloride and 0.7 ml of triethylamine were added at 0° C.to a mixture of 2.6 g of the product of Step B and 26 ml of acetone andthe temperature was allowed to rise to room temperature. The mixture wasstirred for one hour to obrain a suspension of mixed anhydride ofp-toluene sulfonic acid and the syn isomer of2-(2-tritylamino-4-thiazolyl)-2-benzyloxyimino-acetic acid which wasused as is for the next step.

Step D: Syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-benzyloxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.

The suspension of Step C was poured into previously cooled solution of1.3 g of 3-methylthiomethyl-7-amino-ceph-3-eme-4-carboxylic acid, 1.4 mlof triethylamine and 13 ml of methylene chloride and the mixture wasstirred at room temperature for 45 minutes. 0.7 ml of acetic acid wereadded to the mixture which was then evaporated to dryness under reducedpressure. The residue was taken up in a mixture of 40 ml of methylenechloride and 40 ml of 0.1N hydrochloric acid and the decanted organicphase was washed with water, dried and evaporated to dryness underreduced pressure to obtain 4.44 g of syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-benzyloxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

Step E: Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl-2-benzyloxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

The product of Step D was taken up in 22 ml of 67% aqueous formic acidand the mixture was stirred for 45 minutes at 45° C. 10 of water wereadded to the mixture which was then filtered and the filtrate wasevaporated to dryness under reduced pressure at 35° C. The residue wastaken up in 50% aqueous ethanol and then with water and vacuum filtered.The product was dried under reduced pressure to obtain 2.28 g of rawproduct which was chromatographed over silica gel and was eluted withaqueous 3M sodium clhoride solution containing 4% of sodium bicarbonate.The organic phase was acidified with N hydrochloric acid and was vacuumfiltered. The product was empasted with water and dried to obtain 0.911g of product. The latter was taken up in 8 ml of methylene chloridecontaining 10% of methanol and a little magnesium sulfate was addedthereto. The mixture was vacuum filtered and the filtrate was evaporatedto dryness under reduced pressure. The residue was taken up in eitherand was vacuum filtered. The product was dried to obtain 0.686 g of puresyn isomer of3-methyl-thiomethyl-7-[2-(2-amino-4-thiazolyl)-2-benzyloxyimino-acetamido]-ceph-3-eme-4-carboxylicacid melting at 168° C. (decomposition).

UV Spectrum (ethanol): Max. at 236 nm: ε=18,100; Inflex. towards 257 nm;Inflex. towards 301 nm: ε=6,700.

UV Spectrum (0.1N HCl-ethanol): Max. at 266 nm: ε=18,800.

NMR Spectrum (DMSO): Peaks at 1.92 ppm (--SCH₃ --); at 3 to 4.16 ppm(--CH₂ --S); at 6.8 ppm (5-hydrogen of thiazole); at 7.41 ppm (hydrogenof phenyl); at 5.2 ppm (hydrogens of --CH₂ φ).

EXAMPLE 18 Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-{2-bromoethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid

Using the procedure of Example 17, 1.909 g of the syn isomer of2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetic acid(described in French Patent No. 2,438,050), 0.68 g of tosyl chloride,0.927 g of 3-methylthiomethyl-7-amino-ceph-3-eme-4-carboxylic acid and15 ml of 67% aqueous formic acid were reacted to obtain 0.615 g of puresyn isomer of3-methyl-thiomethyl-7-[2-(2-amino-4-thiazolyl)-2-{2-bromoethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid with a melting point of 185° C. (decomposition).

UV Spectrum (ethanol): Max. at 232; nm: ε=18,000; Inflex. towards 255nm; Inflex. towards 296 nm: ε=7,600.

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm: ε=18,800; Inflex.towards 280 nm.

NMR Spectrum (DMSO): Peaks at 2 ppm (--SCH₃); at 3.44 to 5.2 ppm(hydrogens of CH₂ --CH₂ Br and CH₂ --SCH₃); at 4.32 to 4.45 ppm(hydrogens of CH₂ CH₂ Br); at 6.9 ppm (5-hydrogen of thiazole).

EXAMPLE 19 Syn isomer of 1-(1-oxopropoxy)-propyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateStep A: Bromopropyl propionate

26.4 ml of propionaldehyde were added over 25 minutes with stirring at5° C. to a mixture of 180 mg of zinc chloride and 30 ml of propionylbromide and the mixture was stirred at room temperature for 15 hours.The mixture was evaporated to dryness under reduced pressure to obtain14.27 g of syn isomer of bromopropyl propionate which was used as is forthe next step.

Step B: Syn isomer of 1-(1-oxopropoxy)-propyl3-methylthio-methyl-7-[2-(2-tritylamino-4-thiazolyl)-{2-methyl-1-methoxy)-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate

3 ml of the product of Step A were added dropwise under an inertatmosphere over 15 minutes to a mixture of 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid, 16.5 ml of dimethylformamide and 0.49 g of potassium carbonate andthe mixture was poured into 200 ml of water. The mixture was extractedwith ethyl acetate and the organic phase was washed with an aqueoussaturated sodium chloride solution, dried and evaporated to drynessunder reduced pressure at less than 40° C. to obrain 6.3 g of raw synisomer of 1-(1-oxopropoxy)-propyl3-methylthio-methyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

Step C: Syn isomer of 1-(1-oxopropoxy)-propyl 3-methyl thio-methylthio-7-/2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido/-ceph-3-eme-4-carboxylate

A mixture of 6.3 g of the product of Step B and 53 ml of a 90% aqueousformic acid solution was stirred for one hour and was filtered and thefiltrate was added to 500 ml of water. The mixture was stirred for 5minutes and was extracted with ethyl acetate. The organic phase waswashed with aqueous saturated sodium chloride solution, dried andevaporated to dryness under reduced pressure to obtain 2.66 g of productwhich was chromatographed over silica gel. Elution was with a 92-8methylene chloride-methanol mixture and the organic phase was evaporatedto dryness. The residue was dissolved in methanol and crystallized fromisopropyl ether to obtain 1.11 g of syn isomer of1-(1-oxopropoxy)-propyl 3-methyl thiomethylthio-7-/2-(2-amino-4-thiazoyl)-2-hydroxyimino-acetamido/-ceph-3-eme-4-carboxylatemelting at 140° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 264 nm E₁ ¹ =347; ε=18,800.

NMR Spectrum (deuterochloroform): Peaks at 2.06 ppm (--SCH₃); at 1.03 to1.26 ppm and 2.21 to 2.56 ppm ##STR55## at 6.83-7.08 ppm (--COOCH--); at0.85 to 1.83 ppm (--CH₂ --CH₃).

EXAMPLE 20 Syn isomer of cyanomethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and 2.2 ml of acetonitrile bromide were reacted to obtain 0.767 gof syn isomer of cyanomethyl3-methyl-thiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatewhich after crystallization from isopropyl ether melted at ˜145° C.

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =367; ε=17,200.

NMR Spectrum (DMSO): Peaks at 2.01 ppm (--SCH₃); at 5.23 ppm (--COOCH₂--); at 6.75 ppm (5-hydrogen of thiazole).

EXAMPLE 21 Syn isomer of 1-(1-oxoethoxy)-propyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.Step A: 3-bromopropyl acetate

40 ml of propionaldehyde were added over 12 minutes at 15° C. to amixture of 37 ml of acetyl bromide and 0.242 g of zinc chloride and themixture was stirred at room temperature for 15 hours. The mixture wasdistilled at 53° to 58° C. at 80 to 90 mmHg and 5 ml of the product and5 ml of chloroform were stirred at room temperature while adding 840 mgof hexamethhylenetetraamine thereto in small fractions. The mixture wasstirred for 10 minutes to obtain a solution of 3-bromo-propyl acetatewhich was used as is for the next step.

Step B: Syn isomer of 1-(1-oxoethoxy) -propyl3-methylthio-methyl-7-[8-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and 7 ml of the solution of Step A were reacted to obtain 0.965 gof pure syn isomer of 1-(1-oxoethoxy)-propyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at 130° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 264 nm E₁ ¹ =347; ε18,400.

NMR Spectrum (deuterochloroform): Peaks at 0.85 to 1.08 ppm (--CH₂--CH₃); at 1.88 to 1.93 ppm (--SCH₃ and ##STR56## at 7.01 ppm(5-hydrogen of thiazole); at 6.83 to 7.16 ppm (COOCHO).

EXAMPLE 22 Syn isomer of 1-acetyloxy ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and 1.55 ml of bromoethyl acetate were reacted to obtain 0.867 g ofsyn isomer of 1-acetyloxy ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at ˜150° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =347; ε=17,800.

MNR Spectrum (deuterochloroform): Peaks at 2.26-2.35 ppm (hydrogens ofCH₃ --CH₂); at 3.06-3.12 ppm (--SCH₃ and OAc); at 5.38 ppm (--CH₂--S--); at 10.4 ppm (5-hydrogen of thiazole).

EXAMPLE 23 Syn isomer of 2-chloro-2-propenyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateStep A: 3-iodo-2-chloro-1-propene

A mixture of 6.1 ml of 2,3-chloro-1-propene, 10 g of sodium iodide and43 ml of acetone was refluxed under an inert atmosphere for 40 minutesand the mixture was cooled to room temperature and was vacuum filteredto obtain a solution of 3-iodo-2-chloro-1-propene which was used as isfor the next step.

Step B: Syn isomer of 2-chloro-2-propenyl3-methylthiomethyl-7-[2-tritylamino-4-thiazolyl)-2-(1-methyl-1-1-methoxy)-ethoxyimino-acetamido]-ceph-3-eme-4-carboxylate

The solution of Step A was added dropwise under an inert atmosphere to asolution of 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid, 16 ml of dimethylformamide and 0.477 g of potassium carbonate andafter 30 minutes, the acetone was distilled under reduced pressure atless than 40° C. 250 ml of isopropyl ether were added to the mixture andthe liquid phase was decanted. The residue was dried under reducedpressure to obtain 7.8 g of syn isomer of 2-chloro-2-propenyl3-methyl-thiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl01-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

Step C: Syn isomer of 2-chloro-2-propenyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of last step of Example 19, th e 7.8 g of theproduct of Step B were reacted to obtain 1.18 g of syn isomer of2-chloro-20-propenyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at ˜146° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =377; ε=19,000.

NMR Spectrum (deuterochloroform): Peaks at 2.03 ppm (SCH₃); at 3.63 ppm(--SCH₂ --); at 4.83 to 5.6 ppm (CH₂ ═ and --COOCH₂ --); at 5.1-5.18 ppm(6-hydrogen).

EXAMPLE 24 Syn isomer of methylthiomethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A; Syn isomer of methylthiomethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate

3.4 ml of chloromethyl methyl sulfide were added dropwise under an inertatmosphere to a solution of 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-}(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid, 16 ml dimethylformamide and 480 mg of potassium carbonate and themixture was stirred for 35 minutes and then poured into 200 ml ofaqueous saturated sodium chloride solution. The mixture was vacuumfiltered and the product was dissolved in chloroform. The solution waswashed with aqueous saturated sodium chloride solution, dried andevaporated to dryness under reduced pressure at less than 40° C. Theresidue was taken up in petroleum ether (b.p. =60°-80° C.) to solidifythe product to obtain 5.2 g of syn isomer of methylthiomethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylatewhich was used as is for the next step.

STEP B: Syn isomer of methylthiomethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

A solution of 5.05 g of the product of Step A in 50 ml of methanol stoodat room temperature for 3 days and was then evaporated to dryness underreduced pressure at less than 40° C. The residue was added to 15 ml ofisopropyl ether and the mixture was stirred at room temperature for 20minutes and was vacuum filtered. The product was rinsed with isopropylether and the 4.5 g of product was chromatographed over silica gel. Theproduct was eluted with a 92-8 methylene chloride-methanol mixture andthe eluant was evaporated to dryness. The residue was added tochloroform and isopropyl ether was added to the solution causeprecipitation. The mixture was filtered and the product was dried toobtain 0.969 g of syn isomer of methylthiomethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at 140° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =379; ε=18,600.

NMR Spectrum (deuterochloroform): Peaks at 2.08 ppm (3-SCH₃); at 2.3 ppm(4-SCH₃); at 5.51 ppm (COOCH₂ --S).

EXAMPLE 25 Syn isomer of 1-(2,2-dimethyl-1-oxopropoxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: 1-iodoethyl tert.-butylcarboxylate

A mixture of 61.4 ml of pivaloyl chloride and 250 mg of zinc chloridewas stirred for 5 minutes and cooled to 15° C. after which 40 ml ofacetaldehyde were added thereto over one hour. The mixture stood at roomtemperature for 15 hours and was evaporated to dryness under reducedpressure to obtain 29.01 g of 2-chloroethyl pivalate distilling at 56°to 58° C. at 27 mm Hg.

7.45 g of sodium iodide were slowly added to 20 ml of tetramethylene andafter stirring the mixture for 10 minutes, 5 ml of 2-chloroethylpivalate were added. The mixture was stirred for 30 minutes at 18° C.for a solution of 1-iodoethyl tert-.butyl-carboxylate.

STEP B: Syn isomer of 1-(2,2-dimethyl-1-oxopropoxy)-ethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]ceph-3-eme-4-carboxylate

3.72 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy)-ethoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid were slowly added under aninert atmosphere to 7.5 ml of tetramethylene and then 0.375 g ofpotassium carbonate and then the product of Step A were added thereto.After one hour, 1.125 g of potassium carbonate were added thereto andthe mixture was stirred for 10 minutes and poured into a mixture of 500ml of water, 250 g of ice and 25 ml of 0.1N hydrochloric acid. Themixture was stirred for 15 minutes and was extracted with ethyl acetate.The organic phase was washed with water and then aqueous saturatedsodium chloride solution, dried and evaporated to dryness under reducedpressure at less than 30° C. The 8.69 g of raw product were added topetroleum ether (b.p.=60°-80° C.) and was filtered to obtain 5.42 g ofsyn isomer of 1-(2,2-dimethyl-1-oxopropoxy)-ethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

STEP C: Syn isomer of 1-(2,2-dimethyl-1-oxopropoxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-ceph-3-eme-4-carboxylate

The product of Step B was added to 55 ml of 88% aqueous formic acid andthe mixture was stirred for 90 minutes and was filtered. The filtratewas poured into 650 ml of ice water and the mixture was extracted withchloroform. The organic phase was washed with water and with aqueoussaturated sodium chloride solution, dried and evaporated to drynessunder reduced pressure at less than 35° C. The 3.04 g of residue waschromatographed over silica gel and was eluted with a 98-2 methylenechloride-methanol mixture. The solution was evaporated to dryness andthe residue was added to chloroform. Precipitation was induced byaddition of isopropyl ether and the mixture was filtered. The productwas dried to obtain 0.733 g of syn isomer of1-(2,2-dimethyl-1-oxopropoxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at ˜140° C.

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 219 nm E₁ ¹ =265; Max.at 265 nm E₁ ¹ =337; ε=18,800.

NMR Spectrum (deuterochloroform): Peaks at 2.06 ppm (CH₃ --S--); at1.19-1.23 ppm (tert.-butyl); at 1.5-1.6 ppm (hydrogens of CH₃ --CH--);at 3.33 ppm and 3.9 ppm (CH₂ S).

EXAMPLE 26 Syn isomer of benzyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: Syn isomer of sodium 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

3.5 ml of a methanolic solution of sodium acetate and 30 ml of ethanolwere added to a solution of 1 g of the syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid in 2 ml of dimethylformamide and the mixture was vacuum filtered.The product was rinsed with ethanol and then with ether to obtain 0.804g of syn isomer of sodium3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

STEP B: Syn isomer of benzyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

0.21 ml of benzyl bromide was slowly added to a mixture of 0.84 g of theproduct of Step A and 4 ml of dimethylformamide and the mixture stood atroom temperature for one hour. 40 ml of water were added thereto and themixture was vacuum filtered. The product was rinsed with water, withisopropyl ether and dried to obtain 0.605 g of product. The latter waschromatographed over silica gel and was eluted with a 95-5 methylenechloride-methanol mixture. The product was crystallized from isopropylether to obtain 0.225 of pure syn isomer of benzyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at 114° C.

UV Spectrum (0.1N HCl-ethanol): Max. at 263-264 nm: ε=19,400.

NMR Spectrum (deuterochloroform): Peaks at 2.01 ppm (--SCH₃); at 7.08ppm (5-hydrogen of thiazole); at 7.43 ppm (hydrogen of phenyl); at 5.3ppm (hydrogens of COOCH₂ --φ).

EXAMPLE 27 Syn isomer of (1-oxohexadecanoxy)-methyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: Iodomethyl palmitate

A mixture of 33 ml of palmitoyl chloride, 3 g of paraformaldehyde and 50mg of zinc chloride was heated at 80° C. under an inert atmosphere for20 minutes and the mixture was then cooled to room temperature and wasvacuum filtered. The product was dissolved in 10 ml of chloroform and100 ml of ethanol were added thereto. The mixture was vacuum filtered toobtain 5 g of chloromethyl palmitate.

A mixture of 4.116 g of the latter product, 2.025 g of sodium iodide and20 ml of acetone was refluxed under an inert atmosphere for 20 minutesand the mixture was cooled to room temperature and filtered to obtain anacetone solution of iodomethyl palmitate which was immediately used inthe next step.

STEP B: Syn isomer of (1-oxohexadecanoxy)-methyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 5 g of the syn isomer of3-methylthiomethyl-7-/2-(2-tritylamino-4-thiazolyl)-2-/(1-methyl-1-methoxy)ethoxyimino-acetamido-ceph-3-eme-4-carboxylicacid and 20 ml of the solution of Step A were reacted to obtain 2.02 gof syn isomer of (1-oxohexadecanoxy)-methyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatewhich after crystallization from petroleum ether (b.p.=60°-80° C.)melted at 125° C.

UV Spectrum (0.1N HCl-ethanol): Max. at 264 nm E₁ ¹ 268; ε=18,700.

NMR (deuterochloroform): Peaks at 0.89 ppm (CH₃ of ester); at 2.37 ppm(CH₂ of ester); at 2.04 ppm (--SCH₃).

EXAMPLE 28 Syn isomer of (2,2-dimethyl-1-oxopropoxy)-methyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Step B of Example 19, 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and an acetone solution of iodomethyl palmitate prepared as in StepA of Example 27 were reacted to obtain after admixture with isopropylether 4.1 g of raw product which was then reacted as in Step C ofExample 19 to obtain 1.98 g of syn isomer of(2,2-dimethyl-1-oxopropoxy)-methyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at 140° C.

UV Spectrum (0.1N HCl-ethanol): Max. at 264 nm E₁ ¹ =325; ε=17,700.

NMR Spectrum (deuterochloroform): Peaks at 2.02 ppm (CH₃ -S-); at 3.61ppm (--CH₂ S--); at 6.93 ppm (5-hydrogen of thiazole); at 1.24 ppm(tert.-butyl).

EXAMPLE 29 Syn isomer of 1-oxopentoxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: Iodomethyl n-valerate

A mixture of 12 g of paraformaldehyde and 48.2 g of n-valeric acidchloride was stirred at 90° C. for 4 hours and 0.3 g of zinc chloridewere added thereto. The mixture was distilled at 71.5°-73° C. at 20 mmHg and 2.94 g of the recovered product were added to 2.25 g of sodiumiodide and 15 ml of acetone. The mixture was refluxed for 20 minutes andwas then cooled to room temperature and was vacuum filtered to obtain anacetone solution of iodomethyl n-valerate which was immediately used inthe next step.

STEP B: Syn isomer of 1-oxopentoxymethyl3-methylthiomethyl-7[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Step B of Example 19, the solution of Step A and3.72 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid were reacted and the mixture was extracted with chloroform. Theorganic phase was washed with aqueous saturated sodium chloride solutionand evaporated to dryness. The residue was added to petroleum ether(b.p.=60°-80° C.) and the mixture was evaporated to dryness. The residuewas admixed with petroleum ether to obtain 4.8 g of the syn isomer of1-oxopentoxymethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

4.7 g of the said product were reacted according to Step C of Example 19with 28.2 ml of a 90% aqueous formic acid solution and after extractionwith chloroform and crystallization from isopropyl ether, 0.6 g of synisomer of 1-oxopentoxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at ˜158° C. were obtained.

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =360; ε=19,600.

NMR Spectrum (deuterochloroform): Peaks at 2.03 ppm (--SCH₃); at 0.82 to0.97 ppm (hydrogens of CH₃ --CH₂); at 2.3 to 2.46 ppm (--COCH₂ --); at6.96 ppm (5-hydrogen of thiazole).

EXAMPLE 30 Syn isomer of 1-oxobutoxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: Iodomethyl n-butyrate

A mixture of 12 g of paraformaldehyde and 42.6 g of n-butyryl chlorideand 1 g of zinc chloride was stirred at room temperature for 3 hours andat 90° C. for 4 hours and was distilled at 180-190 mm Hg to recover thefraction boiling at 104°-107° C. 2.8 g of the said product were slowlyadded to a mixture of 6 ml of tetramethylurea and 3.4 g of sodium iodideand the mixture was stirred for 2 hours and vacuum filtered to obtain asolution of iodomethyl n-butyrate which was immediately used in the nextstep.

STEP B: Syn isomer of 1-oxobutoxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Step B of Example 25, 3.72 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and the solution of Step A were reacted to obtain 4.52 g of productwhich was then reacted with 45 ml of 90% aqueous formic acid by themethod of Step C of Example 25 to obtain 0.627 g of syn isomer of1-oxobutoxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at 160° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 261 nm E₁ ¹ =290;ε=15,300; Max. at 264 nm E₁ ¹ =355; ε=18,800.

NMR Spectrum (deuterochloroform): Peaks at 0.86 to 1.02 ppm (CH₃ ofpropyl); at 2.27 to 2.43 ppm (COCH₂ --); at 5.88 ppm (--COOCH₂ O); at6.94 ppm (5-hydrogen of thiazole).

EXAMPLE 31 Syn isomer of acetyloxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and 20 ml of an acetone solution of iodomethyl acetate preparedextemporaneously from 1.92 g of chloromethyl acetate and 2.67 g ofsodium iodide were reacted and the product was chromatographed oversilica gel. Residual formic acid was removed by entrainment withnitromethane to obtain 1.677 g of pure syn isomer of acetyloxymethyl3-methyl-thiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at ˜120° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 263 nm E₁ ¹ =354; ε=17,800.

NMR Spectrum (DMSO): Peaks at 2 ppm (CH₃ S--); at 2.04 ppm (OAc); at5.86 ppm (COOCH₂ O); at 6.72 ppm (5-hydrogen of thiazole).

EXAMPLE 32 Syn isomer of 3,3-dimethyl-2-oxobutyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Step A of Example 25, 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid, 0.47 g of potassium carbonate, 27 ml of tetramethylurea and 0.95ml of bromopinacolone were reacted to obtain 7.5 g of the syn isomer of3,3-dimethyl-2-oxobutyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

Using the procedure of Step C of Example 25, the 7.5 g of the latterproduct and 53 ml of 90% aqueous formic acid were reacted and afterpurification by chromatography, residual formic acid was removed byentrainment with nitromethane to obtain 1.392 g of syn isomer of3,3-dimethyl-2-oxobutyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at ˜160° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 264 nm E₁ ¹ =388; ε=20,500.

NMR Spectrum (deuterochloroform): Peaks at 1.23 ppm (tert.-butyl); at4.82-5.1 ppm and 5.13-5.41 ppm (COOCH₂ CO).

EXAMPLE 33 Syn isomer of 1-(1-oxopropoxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 9 ml of propionyl bromide and 50 mg of zinc chloride wascooled under reduced pressure at -15° C. and 5.4 ml of acetaldehyde wereadded thereto dropwise. The temperature was allowed to rise to roomtemperature to obtain 5.4 ml of a solution of bromoethyl propionate.Using the procedure of Example 19, the said solution and 10 g of the synisomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid were reacted. The resulting product was treated with formic acidand entrainment with nitromethane removed residual formic acid. The 1.5g of product was chromatographed over silica gel and was eluted with a92.5-7.5 methylene chloride-methanol mixture to obtain 0.566 g of puresyn isomer of 1-(1-oxopropoxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at ˜130° C.

UV Spectrum (0.1N HCl-ethanol): Max. at 264 nm E₁ ¹ =364; ε=19,300.

NMR Spectrum (deuterochloroform): Peaks at 1.5-1.6 ppm (hydrogens of CH₃--CH); at 7.05 ppm (5-hydrogen of thiazole).

EXAMPLE 34 Syn isomer of 1-(1-oxobutoxy)-ethyl3methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: Iodoethyl butyrate

A mixture of 52 ml of butyryl chloride and 31 ml of acetaldehyde wereplaced in a flask at 16° C. under an inert atmosphere and 0.11 g offernic chloride were added. The flask was hermetically sealed and themixture stood at room temperature for 18 hours and was then poured into200 ml of petroleum ether (b.p.=60°-80° C.). The mixture was treatedwith activated carbon and filtered and the filtrate was evaporated todryness under reduced pressure at less than 30° C. to obtain chloroethylbutyrate as the fraction distilling between 64° to 68° C. at 34 mmHg.

4 g of sodium iodide were added piecemeal to a mixture of 4 g of thesaid product in 16 ml of dimethylacetamide and the mixture was stirredfor 15 minutes to obtain a solution of iodoethyl butyrate which wasimmediately used in the next step.

STEP B: Syn isomer of 1-(1-oxo-butoxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 5 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid in dimethylacetamide instead of dimethylformamide and the solutionof Step A were reacted and the product was purified by chromatography.Residual formic acid was removed by entrainment with nitromethane toobtain 0.530 g of pure syn isomer of 1-(1-oxo-butoxy)-ethyl3-methylthiomethyl-7[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at 127° C.

UV Spectrum (0.1N HCl-ethanol): Max. at 264 nm E₁ ¹ =353; ε=19,200.

NMR Spectrum (deuterochloroform): Peaks at 0.87 to 1.03 ppm (hydrogensof CH₃ --CH₂ --CH₂ --); at 1.54-1.6 ppm (hydrogens of CH₃ --CH═); at2.09 ppm (hydrogens of CH₃ S--); at 7.08 ppm (5-hydrogen of thiazole).

EXAMPLE 35 Syn isomer of 1-(1-oxohexadecyloxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 25, 744 mg of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid, 1.5 ml of tetramethylurea, 78 mg of potassium carbonate and anextemporaneously made solution of iodoethyl palmitate in tetramethylureawere reacted and then another 210 mg of potassium carbonate were addedthereto. The mixture was extracted with chloroform which was distilledto dryness. The residue was taken up in 45 ml of 98% aqueous formic acidand the mixture was extracted with chloroform. The organic phase wasevaporated to dryness and the residue was treated with petroleum ether(b.p.=60°-80° C.) to obtain 0.353 g of syn isomer of1-(1-oxohexadecyloxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at 108° C.

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 218 nm E₁ ¹ =215; Max.at 265 nm E₁ ¹ =266; ε=18,900.

NMR Spectrum (deuterochloroform): Peaks at 0.88 ppm (CH₃ --CH₂ --CH₂--); at 1.5-1.6 ppm (hydrogens of CH₃ CH═); at 2.06 ppm (hydrogens ofCH₃ S--); at 3.63 ppm (--CH₂ --S--).

EXAMPLE 36 Syn isomer of 2-propenyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 3.72 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid in dimethylacetamide in place of dimethylformamide and 1.85 ml ofallyl chloride were reacted to obtain 1.128 g of pure syn isomer of2-propenyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting ˜137° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 262 nm E₁ ¹ =393; ε=18,500.

NMR Spectrum (deuterochloroform): Peaks at 2.08 ppm (CH₃ S--); at4.73-4.83 ppm (COOCH₂ --); at 5.08 to 6.5 ppm (--C═CH₂ and hydrogen ofβ-lactam); at 7.08 ppm (5-hydrogen of thiazole).

EXAMPLE 37 Syn isomer of 2,2-dimethylethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 1.49 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid, 30 ml of ethyl acetate and 0.8 g ofO-tert.-butyl-N,N'-diisopropylurea was heated to reflux and then wasiced and vacuum filtered. The filtrate was evaporated to dryness underreduced pressure to obtain the syn isomer of 2,2-dimethylethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

The said product was taken up in 7.5 ml of 67% aqueous formic acid andthe mixture was stirred for 15 minutes at 45° C. 3 ml of water wereadded to the mixture which was vacuum filtered and the filtrate wasevaporated to dryness under reduced pressure at 35° C. The residue wastaken up in a 1-1 water-ethanol mixture and then water was addedthereto. The product was dried to obtain 1.237 g of raw product whichwas chromatographed over silica gel. Elution with a 9-1 methylenechloride-methanol mixture yielded 0.47 g of pure syn isomer of2,2-dimethylethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylatemelting at 107° C. (decomposition).

UV Spectrum (ethanol): Max. at 223 nm: ε=18,000; Max. at 260 nm:ε=13,500.

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 220 nm; Max. at 264 nm:ε=18,600.

NMR Spectrum (deuterochloroform): Peaks at 1.54 ppm (tert.-butyl); at2.11 ppm (hydrogens of CH₃ S--); at 7.08 ppm (5-hydrogen of thiazole).

EXAMPLE 38 Syn isomer of 2-methoxy-2-oxoethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 1.6 ml of methyl monochloroacetate, 2.72 g of sodium iodideand 20 ml of acetone was refluxed under an inert atmosphere for 25minutes and was then vacuum filtered to obtain a solution of iodomethylacetate which was immediately used. Using the procedure of Example 19,10 ml of the said solution and 3.44 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid were reacted to obtain 2.8 g of 2-methoxy-2-oxoethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

The said product was triturated at 60° C. for 10 minutes with 5.6 ml ofpure formic acid and 16.8 ml of 50% aqueous formic acid and was thenfiltered. The filtrate was entrained with nitromethane to removeresidual formic acid and was then dried and evaporated to dryness. Theresidue was taken up in chloroform and isopropyl ether was added to thesolution to cause precipitation. The mixture was filtered and theproduct was dried to obtain 1.65 g of raw product which was added to amixture of 90 ml of ethyl acetate and 90 ml of 0.1N hydrochloric acid.The mixture was extracted with ethyl acetate and the organic phases wereevaporated to dryness. The residue was dissolved in chloroform andisopropyl ether was added to the solution to cause precipitation. Theproduct was chromatographed over silica gel and was eluted with a92.5-7.5 methylene chloride-methanol mixture to obtain 0.4 g of pure synisomer of 2-methoxy-2-oxoethyl 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate meltingat 156° C. (decomposition).

UV Spectrum (0.1N HCl-ethanol): Max. at 264 nm E₁ ¹ =383; ε=19,200.

NMR Spectrum (deuterocholoroform): Peaks at 2.07 ppm (--SCH₃); at 3.68ppm (--S--CH₂ --); at 3.8 ppm (hydrogens of --COOCH₃); at 7 ppm(5-hydrogen of thiazole).

EXAMPLE 39 Syn isomer of 1-(acetyloxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 10.92 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid, 55 ml of dimethylformamide and 1.28 g of potassium carbonate wasstirred at 20° C. for 15 minutes and after cooling the mixture to 5° C.,3.4 ml of 1-bromoethyl acetate were added thereto. The mixture wasstirred for 20 minutes and then 0.1 g of potassium carbonate and 0.3 mlof 1-bromoethyl acetate were added thereto. The mixture was stirred for25 minutes and 550 ml of water, 150 ml of ethyl acetate and 25 ml of 1Maqueous sodium bicarbonate solution were added thereto. The decantedaqueous phase was extracted with ethyl acetate and the organic phase wasdried and evaporated to dryness under reduced pressure at less than 30°C. to obtain 14.3 g of the syn isomer of 1-(acetyloxy)-ethyl3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.

A solution of 14.3 g of the said product in 61 ml of 66% aqueous formicacid was stirred at 50° C. for 10 minutes and 24 ml of water were addedthereto. The mixture was filtered and the filtrate was evaporated todryness under reduced pressure. The residue was taken up in a mixture of50 ml of methylene chloride, 350 ml of water and 10 ml of aqueous sodiumbicarbonate solution and was extracted with methylene chloride. Theorganic phase was washed with water, dried and evaporated to dryness.The residue was taken up in ethyl acetate and the mixture was vacuumfiltered. The product was dried to obtain 4.87 g of syn isomer of1-(acetyloxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

UV Spectrum (ethanol): Max. at 223 nm E₁ ¹ =387; ε=19,300; Max. at 259nm E₁ ¹ =285; ε=14,200.

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 219 nm E₁ ¹ =286; Max.at 261-262 nm E₁ ¹ =390; ε=19,500.

NMR Spectrum (DMSO): Peaks at 1.43-1.51 ppm (hydrogens of CH₃ --CH--);at 2.08 ppm (OAc); at 3.58 ppm (--CH₂ --S); at 3.25 ppm (OCH₃); at 6.75ppm (5-hydrogen of thiazole).

EXAMPLE 40 Syn isomer of 1-(1-oxoethoxy)-ethyl3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 39, 6 g of the syn isomer of3-ethoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and 2.1 ml of 1-bromoethyl acetate were reacted to obtain 1.76 g ofsyn isomer of 1-(1-oxoethoxy)-ethyl3-ethoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

UV Spectrum (ethanol): Inflex. towards 220 nm E₁ ¹ =268; Max. at 264 nmE₁ ¹ =369; ε=18,900.

UV Spectrum (0.1N HCl-ethanol): Inflex. towards 219 nm E₁ ¹ =286; Max.at 261 nm E₁ ¹ =390; ε-19,500.

NMR Spectrum (DMSO): Peaks at 1-1.12-1.23 ppm (CH₃ of ethoxy); at1.45-1.53 ppm (hydrogens of CH₃ --CH); at 2.06 ppm (OAc); at 6.73 ppm(5-hydrogen of thiazole).

EXAMPLE 41 Syn isomer of 1-methoxycarbonyloxy-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: Iodomethyl methylcarbonate

Chlorine was bubbled through 200 ml of ethyl chloroformate for 8 hoursand the flask was hermetically sealed. The mixture stood at roomtemperature for 5 days and was then distilled at 50 mm Hg to recover thefraction boiling at 42° to 46° C. which was 1-chloroethyl chloroformate.5 ml of the said product and 16 ml of methanol were stirred under aninert atmosphere at room temperature for one hour to obtain a solutioncontaining chloromethyl methylcarbonate. The mixture was added to 38 mlof acetone and 10.9 g of sodium iodide were added thereto. The mixturewas refluxed for 5 minutes and then returned to room temperature. Themixture was evaporated to dryness under reduced pressure at less than 40° C. and the residue was added to a mixture of 100 ml of ether and 75 mlof water. The decanted aqueous phase was extracted with ether and theorganic phases were washed with water and with aqueous 0.25M sodiumbisulfite solution, then with water and aqueous saturated sodiumchloride solution, dried and evaporated to dryness under reducedpressure at no more than 40° C. to obtain iodoethyl methylcarbonatewhich was immediately used in the next step.

STEP B: Syn isomer of 1-methoxycarbonyloxy-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 3.2 g of the product of Step A and3.72 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid were reacted to obtain 1.12 g of pure syn isomer of1-methoxycarbonyloxy-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =365; ε=19,400.

NMR Spectrum (deuterochloroform): Peaks at 1.53-1.63 ppm (hydrogens ofCH₃ --CH); at 2.06 ppm (S--CH₃); at 3.83 ppm (--COOCH₃); at 7.05 ppm(5-hydrogen of thiazole); at 6.75 to 7.16 ppm (hydrogen of --CH--CH₃).

EXAMPLE 42 Syn isomer of 1-ethoxycarbonyloxy-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid and iodomethyl ethylcarbonate prepared using a procedure similar toStep A of Example 41 were reacted to obtain syn isomer of1-ethoxycarbonyloxy-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

NRM Spectrum (deuterochloroform): Peaks at 1.2 to 1.45 ppm (CH₃ -- ofCOOCH₂ --CH₃); at 1.55-1.64 ppm (hydrogens of CH₃ --CH--); at 6.9 ppm(5-hydrogen of thiazole); at 2.08 ppm (--SCH₃).

EXAMPLE 43 Syn isomer of methoxycarbonyloxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateSTEP A: MONOIDO CARBONATE

Chlorine was bubbled for 5 hours through 30 ml of dimethylcarbonateheated to 65° C. under an inert atmosphere and the mixture was thenallowed to stand for 56 hours. The mixture was distilled at 50 mm Hg toobtain 7.8 ml of monochlorocarbonate boiling at 59° to 61° C. A mixtureof 5 ml of the said product, 7.8 g of sodium iodide and 30 ml of acetonewas heated at 30° C. for 90 minutes and was then evaporated to dryness.The residue was added to a mixture of 100 ml of water and 100 ml ofether and the mixture was stirred for 5 minutes. The decanted aqueousphase was extracted with ether and the organic phase was washed withaqueous 0.25M sodium bisulfite solution, with water and with aqueoussaturated sodium chloride solution, was dried and evaporated to drynessunder reduced pressure at not more than 40° C. to obtain 7.93 g ofmonoiodocarbonate which was immediately used in the next step.

STEP B: Syn isomer of methoxycarbonyloxymethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

Using the procedure of Example 19, 7.93 g of the product of Step A and 5g of the syn isomer of 3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid were reacted to obtain 0.537 g of pure syn isomer ofmethoxycarbonylmethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.

UV Spectrum (0.1N HCl-ethanol): Max. at 265 nm E₁ ¹ =371; ε=19,200.

NMR Spectrum (deuterochloroform): Peaks at 2.03 ppm (SCH₃); at 3.85 ppm(COOCH₃); at 6.96 ppm (5-hydrogen of thiazole); at 5.91 ppm (COOCH₂).

EXAMPLE 44 Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-carboxymethoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: Syn isomer of triethylamine3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate

A solution of 14.88 g of the syn isomer of3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-{(1-methyl-1-methoxy)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylicacid, 20 ml of 2N hydrochloric acid and 60 ml of acetone was stirred for70 minutes at room temperature and the acetone was distilled. Themixture was diluted with 100 ml of water and was vacuum filtered and theproduct was washed with water and added to a mixture of 60 ml of acetoneand 6 ml of water. 2.8 ml of triethylamine were added to the mixture andcrystallization was induced. 20 ml of acetone were added which causedefflorescence and the mixture was vacuum filtered. The product wasempasted with water and then with ether to obtain a first yield of 11.4g of syn isomer of triethylamine3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.Then, after the residue was taken up in acetone, another 0.85 g ofproduct was obtained for a total yield of 12.25 g.

NMR Spectrum (DMSO): Peaks at 1.96 ppm (hydrogens of CH₃ S--); at 6.66ppm (5-hydrogen of thiazole); at 7.36 ppm (trityl protons).

STEP B: Syn isomer of triethylamine3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1,1-dimethylethoxycarbonyl-methoxyimino)-acetamido]-ceph-3-eme-4-carboxylate

A mixture of 3.09 g of the product of Step A, 30 ml of demineralizedwater and 60 ml of methylene chloride was admixed at 20° C. with 5 ml oftriethylamine and 4.8 g of tert.-butyl bromoacetate and the mixture wasstirred at 20°-25° C. for 21/2 hours. The mixture was acidified byaddition of 10 ml of 2N hydrochloric acid and the decanted organic phasewas washed twice with 100 ml of water. The wash waters were reextractedtwice with 20 ml of methylene chloride and the combined organic phaseswere dried and filtered. The filtrate was evaporated to dryness underreduced pressure and the residue was empasted with ether and the mixturewas vacuum filtered. The product was rinsed with ether and dried at 20°C. under reduced pressure to obtain 3 g of the acid. The latter wastaken up in a mixture of 7.5 ml of benzene and 0.7 ml of triethylamineand 75 ml of ether were added to the resulting solution. The mixture wasvacuum filtered and the product was rinsed 3 times with 2 ml of etherand dried to obtain 2.4 g of syn isomer of triethylamine3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1,1-dimethylethoxycarbonylmethoxyimino)-acetamido]-ceph-3-eme-4-carboxylatewhich was used as for the next step.

NMR Spectrum (deuterochloroform): Peaks at 2.04 ppm (hydrogens of CH₃S--); at 4.76 ppm (hydrogens of ═N--O--CH₂ --); at 6.9 ppm (5-hydrogenof thiazole); at 7.36 ppm (trityl protons).

STEP C: Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-carboxymethoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

A mixture of 2.3 g of the product in Step B and 11.5 ml oftrifluoroacetic acid was stirred for 25 minutes at 20° C. and themixture was distilled in a water bath until the majority of thetrifluoroacetic acid was gone. 100 ml of isopropyl ether were added tothe mixture with cooling and the mixture was stirred at 20° C. for 30minutes and was then vacuum filtered. The product was rinsed withisopropyl ether and dried to obtain 1.957 g of raw product which wasdissolved in a mixture of 5 ml of an aqueous 1M sodium bicarbonatesolution and 0.3 ml of triethylamine. 5 ml of aqueous saturated sodiumchloride solution were added thereto and the mixture was chromatographedover silica gel. Elution was with aqueous 2M sodium chloride solutioncontaining 4‰ of 1M sodium bicarbonate solution and the pH thereof wasadjusted to 4 by addition of 50% aqueous formic acid. The resultingproduct was washed and dried to obtain 0.376 n of syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-carboxymethoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

Analysis: C₁₆ H₁₇ O₇ N₅ S₃ : molecular weight=487.534;Calculated: %C39.42; %H 3.51; %N 14.36; %S 19.73; Found: %C 39.6; %H 3.7; %N 14.2; %S18.7.

NMR Spectrum (DMSO): Peaks at 2 ppm (CH₃ --S--); at 4.63 ppm (hydrogensof N--O--CH₂ --); at 6.85 ppm (5-hydrogen of thiazole).

EXAMPLE 45 Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-ethoxycarbonyloxyimino-acetamido]-ceph-3-eme-4-carboxylicacid STEP A: Syn isomer of triethylamine3-methylthiomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-ethoxycarbonyloxyimino-aceteamido]-ceph-3-eme-4-carboxylate.

0.6 ml of ethyl chloroformate were added over 3 minutes at roomtemperature to a mixture of 2.32 g of the triethylamino salt of Step Aof Example 44, 23 ml of dry methylene chloride and 0.5 ml of pyridineand after the mixture stood at room temperature for 15 minutes, 25 ml ofwater containing 6 ml of N hydrochloric acid were added thereto. Thedecanted aqueous phase was rinsed with 5 ml of methylene chloride andthe combined organic phases were dried and vacuum filtered. The filterwas rinsed with methylene chloride and the filtrate was evaporated todryness. The residue was taken up in 20 ml of ethyl acetate and themixture was stirred until total dissolution occured. 0.5 ml oftriethylamine were added to the mixture and the mixture was vacuumfiltered. The product was rinsed with ethyl acetate and ether and wasdried to obtain 1.49 g of syn isomer of triethylamine3-methylthiomethyl-7-[2-tritylamino-4-thiazolyl)-2-ethoxycarbonyloxyimino-acetamido]-ceph-3-eme-4-carboxylate.

STEP B: Syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-ethoxycarbonyloxyimino-acetamido]-ceph-3-eme-4-carboxylicacid

The product of Step A was added to 7.6 ml of 67% aqueous formic acid andthe mixture was stirred at 45° C. for 10 minutes and was vacuumfiltered. The product was rinsed with 67% aqueous formic acid and driedto obtain 0.434 g of product. The filtrate was evaporated to drynessunder reduced pressure at 35° C. and the residue was taken up in waterand efflorescence occured. The mixture was vacuum filtered and theproduct was rinsed with water and was combined with 0.319 g of rawproduct produced in the same way. The product was dissolved in anaqueous 0.5M sodium bicarbonate solution and was chromatographed oversilica gel. The product was eluted with aqueous 3M sodium chloridesolution containing 4‰ of sodium bicarbonate solution and the fractionwith the desired product was adjusted to a pH of 3 by addition of aceticacid. The mixture stood at room temperature for 30 minutes and wasvacuum filtered. The product was empasted 4 times with water and driedunder reduced pressure to obtain 0.708 g of syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-ethoxycarbonyloxyimino-acetamido]-ceph-3-eme-4-carboxylicacid.

Analysis: C₁₇ H₁₉ O₇ N₅ S₃ ; molecular weight=501.56;Calculated: %C40.7; %H 3.8; %N 14.0; %S 19.2; Found: %C 40.7; %H 3.7; %N 13.9; %S19.3;

NMR Spectrum (DMSO): Peaks at 1.26 ppm (t: J=7 Hz) (hydrogens of COOCH₂--CH₃); at 2 ppm (hydrogens of CH₃ --S--); at 4.25 ppm (q: J=7 Hz)(hydrogens of COOCH₂ --CH₃); at 7.11 ppm (5-hydrogen of thiazole.)

EXAMPLE 46

Injectable preparations were prepared containing 500 mg of either thesyn isomer of3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylicacid or the syn isomer of3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylicacid and sufficient sterile aqueous excipient for a final volume of 5ml.

Gelules were prepared containing 250 mg of either the syn isomer of(1-oxopropoxy)-methyl3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateor the syn isomer of (1-oxopropoxy)-methyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-ceph-3-eme-4-carboxylateor the syn isomer of 1-(acetyloxy)- ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateor the syn isomer of 1-(methoxycarbonyloxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateor the syn isomer of 1-(ethoxycarbonyloxy)-ethyl3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylateand sufficient excipient for a final gelule of 400 mg.

PHARMACOLOGICAL STUDY A. In Vitro Activity

A series of tubes were prepared containing the same amounts of sterilenutritive medium and each tube then received increasing amounts of thetest compounds after which each tube was seeded with a bacterial strain.After incubation for 24 or 48 hours in an oven at 37° C., the inhibitionwas determined by transillumination to determine the minimum inhibitoryconcentration (M.P.C.) expressed in mg/ml. The results are shown in thefollowing Table.

    ______________________________________                                        PRODUCT OF EXAMPLE 1                                                                                M.I.C.                                                                        in μg/ml                                             STRAINS                 24 h   48 h                                           ______________________________________                                        Staphylococcus aureus ATCC 6 538                                                                      1      1                                              Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                        0,5    1                                              Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                             0,5    2                                              Streptococcus pyogenes A 561                                                                          0,2    0,2                                            Streptococcus faecalis 5 432                                                                          10     10                                             Streptococcus faecalis 99 F 74                                                                        10     20                                             Bacillus subtilis ATCC 6 633                                                                          1      2                                              Escherichia Coli Sensible Tetracycline                                                                1      1                                              ATCC 9 637                                                                    Escherichia Coli Resistant Tetracycline                                                               0,5    0,5                                            ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                               0,5    1                                              Escherichia Coli Resistant Gentamicine                                                                1      1                                              Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                     0,2    0,5                                            Klebsiella pneumoniae 2 536 Resistant                                                                 0,5    1                                              Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                      0,3    0,5                                            Salmonella typhimurium 420                                                                            0,5    1                                              ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 2                                                                              M.I.C.                                                                        in μg/ml                                               STRAINS               24 h    48 h                                            ______________________________________                                        Staphylococcus aureus ATCC 6 538                                                                    3       5                                               Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      5       10                                              Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           3       5                                               Streptococcus pyogenes A 561                                                                        0,3     0,5                                             Bacillus subtilis ATCC 6 633                                                                        10      20                                              Escherichia Coli Sensible Tetracycline                                                              20      20                                              ATCC 9 637                                                                    Escherichia Coli Resistant Tetracycline                                                             3       3                                               ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             2       3                                               Escherichia Coli Resistant Gentamicine                                                              5       10                                              Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   3       3                                               Klebsiella pneumoniae 2 536 Resistant                                                               20      20                                              Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                    3       3                                               Salmonella typhimurium 420                                                                          5       5                                               ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 3                                                                              M.I.C.                                                                        in μg/ml                                               STRAINS               24 h    48 h                                            ______________________________________                                        Staphylococcus aureus ATCC 6 538                                                                    1       2                                               Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      3       3                                               Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           2       2                                               Streptococcus pyogenes A 561                                                                        ≦0,02                                                                          ≦0,02                                    Streptococcus faecalis 5 432                                                                        20      40                                              Streptococcus faecalis 99 F 74                                                                      20      >40                                             Bacillus subtilis ATCC 6 633                                                                        1       3                                               Escherichia Coli Sensible Tetracycline                                                              1       1                                               ATCC 9 637                                                                    Escherichia Coli Resistant Tetracycline                                                             0,1     0,1                                             ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             0,2     0,2                                             Escherichia Coli Resistant Gentamicine                                                              0,5     0,5                                             Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                    0,05   0,1                                             Klebsiella pneumoniae 2 536 Resistant                                                               0,5     0,5                                             Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                     0,05    0,05                                           Salmonella typhimurium 420                                                                          0,5     0,5                                             Providencia DU 48     5       5                                               Serratia Resistant Gentamicine 2 532                                                                2       2                                               ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 4                                                                              M.I.C.                                                                        in μg/ml                                               STRAINS               24 h    48 h                                            ______________________________________                                        Staphylococcus aureus ATCC 6 538                                                                    0,2     0,5                                             Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      0,5     0,5                                             Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           0,2     0,5                                             Streptococcus pyogenes A 561                                                                        ≦0,02                                                                          ≦0,02                                    Streptococcus faecalis 5 432                                                                        5       10                                              Streptococcus faecalis 99 F 74                                                                      3       10                                              Bacillus subtilis ATCC 6 633                                                                        0,5     1                                               Escherichia Coli Sensible Tetracycline                                                              2       3                                               ATCC 9 637                                                                    Escherichia Coli Resistant Tetracycline                                                             0,2     0,5                                             ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             0,5     0,5                                             Escherichia Coli Resistant Gentamicine                                                              1       1                                               Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   0,2     0,2                                             Klebsiella pneumoniae 2 536 Resistant                                                               2       3                                               Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                    0,5     1                                               Salmonella typhimurium 420                                                                          1       1                                               ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 6                                                                              M.I.C.                                                                        in μg/ml                                               STRAINS               24 h    48 h                                            ______________________________________                                        Staphylococcus aureus ATCC 6 538                                                                    1         2                                             Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      2         2                                             Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           2         2                                             Streptococcus pyogenes A 561                                                                        0,05    0,05                                            Streptococcus faecalis 5 432                                                                        1       >40                                             Streptococcus faecalis 99 F 74                                                                      2       >40                                             Bacillis subtilis ATCC 6 633                                                                        1         2                                             Escherichia Coli Sensible Tetracycline                                                              3         3                                             ATCC 9 637                                                                    Escherichia Coli Resistant Tetracycline                                                             0,5     0,5                                             ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             1         1                                             Escherichia Coli Resistant Gentamicine                                                              1         1                                             Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   0,1     0,1                                             Klebsiella pneumoniae 2 536 Resistant                                                               2         2                                             Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                    0,2     0,2                                             Salmonella typhimurium 420                                                                          1         2                                             Serratia Resistant Gentamicine 2 532                                                                2         3                                             ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 7                                                                              M.I.C.                                                                        in μg/ml                                               STRAINS               24 H    48 H                                            ______________________________________                                        Staphylococcus aureus ATCT 6 538                                                                    0,2     0,5                                             Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      0,5     0,5                                             Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           0,2     0,5                                             Streptococcus pyrogenes A 561                                                                       ≦0,02                                                                          ≦0,02                                    Streptococcus faecalis 5 432                                                                        10      20                                              Streptococcus faecalis 99 F 74                                                                      3       20                                              Escherichia Coli Sensible                                                                           3       3                                               Tetracycline 7624                                                             Escherichia Coli Resistant Tetracycline                                                             1       1                                               ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             2       2                                               Escherichia Coli Resistant Gentamicine,                                                             5       5                                               Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   1       1                                               Klebsiella pneumoniae 2 536 Resistant                                                               10      10                                              Gentamycine                                                                   Proteus mirabilis (indol+) A 235                                                                    1       2                                               Salmonella typhimurium 420                                                                          5       5                                               ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 8                                                                              M.I.C.                                                                        in μg/ml                                               STRAINS               24 H    48 H                                            ______________________________________                                        Staphylococcus aureus ATCT 6 538                                                                    0,5     0,5                                             Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      1       1                                               Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           0,5     1                                               Streptococcus pyrogenes A 561                                                                        0,05    0,05                                           Streptococcus faecalis 5 432                                                                        5       10                                              Streptococcus faecalis 99 F 74                                                                      2       10                                              Escherichia Coli Sensible Tetracycline 7624                                                         1       1                                               Escherichia Coli Resistant Tetracycline                                                             0,5     0,5                                             ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             0,5     1                                               Escherichia Coli Resistant Gentamicine,                                                             1       1                                               Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   0,5     0,5                                             Klebsiella pneumoniae 2 536 Resistant                                                               2       3                                               Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                    0,5     1                                               Salmonella typhimurium 420                                                                          1       1                                               ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 17                                                                             M.I.C.                                                                        in μg/ml                                               STRAINS               24 H    48 H                                            ______________________________________                                        Staphylococcus aureus ATCT 6 538                                                                    0,5     0,5                                             Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      0,5     0,5                                             Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           1       1                                               Streptococcus pyrogenes A 561                                                                       ≦0,02                                                                          ≦0,02                                    Escherichia Coli Sensible Tetracycline 7624                                                         3       5                                               Escherichia Coli Resistant Tetracycline                                                             3       5                                               ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             2       2                                               Escherichia Coli Resistant Gentamicine,                                                             3       3                                               Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   0,5     1                                               Klebsiella pneumoniae 2 536 Resistant                                                               10      10                                              Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                    1       2                                               Salmonella typhimurium 420                                                                          1       5                                               ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 18                                                                             M.I.C.                                                                        in μg/ml                                               STRAINS               24 H    48 H                                            ______________________________________                                        Staphylococcus aureus ATCT 6 538                                                                    0,5     0,5                                             Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      1       2                                               Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           1       1,5                                             Streptococcus pyrogenes A 561                                                                       ≦0,02                                                                          ≦0,02                                    Escherichia Coli Sensible Tetracycline 7624                                                         3       5                                               Escherichia Coli Resistant Tetracycline                                                             1       2                                               ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             3       3                                               Escherichia Coli Resistant Gentamicine,                                                             2       2                                               Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   0,5     0,5                                             Klebsiella pneumoniae 2 536 Resistant                                                               10      10                                              Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                    1       2                                               Salmonella typhimurium 420                                                                          3       5                                               ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 44                                                                             M.I.C.                                                                        in μg/ml                                               STRAINS               24 H    48 H                                            ______________________________________                                        Staphylococcus aureus ATCT 6 538                                                                    3       5                                               Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      5       5                                               Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           5       10                                              Streptococcus pyrogenes A 561                                                                       0,2     0,2                                             Escherichia Coli Sensible Tetracycline 7624                                                         1       2                                               Escherichia Coli Resistant Tetracycline                                                             0,2     0,5                                             ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             0,5     0,5                                             Escherichia Coli Resistant Gentamicine,                                                             2       2                                               Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   0,2     0,5                                             Klebsiella pneumoniae 2 536 Resistant                                                               1       1                                               Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                     0,05   0,1                                             Proteus vulgaris (indol+) A 232                                                                     0,1     0,1                                             Salmonella typhimurium 420                                                    PROVIDENCIA DU 48     1       5                                               SERRATIA RESISTANT    1       1                                               GENTAMICINE 2 532                                                             ______________________________________                                    

    ______________________________________                                        PRODUCT OF EXAMPLE 45                                                                             M.I.C.                                                                        in μg/ml                                               STRAINS               24 H    48 H                                            ______________________________________                                        Staphylococcus aureus ATCT 6 538                                                                    0,5     0,5                                             Penicillin Sensitive                                                          Staphylococcus aureus UC 1 128                                                                      1       1                                               Penicillin Resistant                                                          Staphylococcus aureus exp. n.sup.o 54 146                                                           0,5     1                                               Streptococcus pyrogenes A 561                                                                       ≦0,02                                                                          ≦0,02                                    Streptococcus faecalis 5 432                                                                        10      10                                              Streptococcus faecalis 99 F 74                                                                      3       10                                              Escherichia Coli Sensible Tetracycline 7624                                                         1       2                                               Escherichia Coli Resistant Tetracycline                                                             0,5     0,5                                             ATCC 11 303                                                                   Escherichia Coli Exp. TO.sub.26 B.sub.6                                                             1       1                                               Escherichia Coli Resistant Gentamicine,                                                             1       1                                               Tobramycine R 55 123 D                                                        Klebsiella pneumoniae Exp. 52 145                                                                   0,2     0,5                                             Klebsiella pneumoniae 2 536 Resistant                                                               3       3                                               Gentamycine                                                                   Proteus mirabilis (indol-) A 235                                                                    0,5     1                                               Salmonella typhimurium 420                                                                          2       2                                               SERRATIA RESISTANT    3       5                                               GENTAMICINE 2 532                                                             ______________________________________                                    

In the following Table, the strains used were as follows:

    ______________________________________                                        Strain A                                                                              Staphylococcus aureus ATCC 6 538                                              Penicillin Sensitive                                                  Strain B                                                                              Staphylococcus aureus UC 1 128 Penicillin Resistance                  Strain C                                                                              Staphylococcus aureus exp. n.sup.o 54 146                             Strain D                                                                              Streptococcus pyogenes A 561                                          Strain E                                                                              Bacillus subtilis ATCC 6 633                                          Strain F                                                                              Escherichia Coli Resistant Tetracycline                                       ATCC 11 303                                                           Strain G                                                                              Escherichia Coli Exp. T026B6                                          Strain H                                                                              Escherichia Coli Resistant Gentamicine                                        Tobramycine R 55 123 D                                                Strain I                                                                              Klebsiella pneumoniae Exp. 52 145                                     Strain J                                                                              Klebsiella pneumoniae 2 536 Resistant Gentamycine                     Strain K                                                                              Proteus mirabilis (Indol-) A 235                                      Strain L                                                                              Proteus vulgaris A 232                                                Strain M                                                                              Salmonella typhimurium 420                                            ______________________________________                                    

The results in the following Table are expressed in mice after 24 hoursof incubation.

    __________________________________________________________________________    STRAINS   A B C D   E F G H I J K L  M                                        __________________________________________________________________________    Product of Example                                                             9        2 2 2 ≦0,02                                                                      3 1 1 2 0,5                                                                             3 0,2                                                                             10 2                                        10        1 2 1 ≦0,02                                                                      2 0,5                                                                             1 1 1 3 0,5                                                                             2  2                                        11        2 3 2 ≦0,02                                                                      2 0,5                                                                             1 1 1 3 0,5                                                                             2  2                                        12        2 3 2  0,05                                                                             5 1 3 3 1 5 1 5  3                                        13        1 2 1 ≦0,02                                                                      1 2 5 5 2 10                                                                              1 -- 3                                        14        3 10                                                                              3  0,05                                                                             2 0,5                                                                             1 1 0,2                                                                             3 0,2                                                                             2  2                                        __________________________________________________________________________

B. In Vivo Antibiotic Activity

Groups of 10 male mice of Charles River CDI strain weighing about 21 to22 g were interperitoneally infected with 0.5 ml of a 22 hour culture ofa strain of Staphylococcus aureus No. 54, 146 (antibiotic medium 3 witha pH of 7) diluted 1/6 with physiological water. The products wereorally administered at different doses in 0.5 ml of distilled water byintubation one, 5 and 24 hours after the injection. The number of micesurviving after 10 days were determined and the results are reported inthe following Table.

    ______________________________________                                        Product of   Oral dose No. of mice living                                     Example      in mg     on 10th day                                            ______________________________________                                         5           0,1       2                                                                    0,25     9                                                                   0,5       10                                                     22           0,1       9                                                                    0,25     10                                                                  0,5       10                                                     28           0,1       1                                                                    0,25     7                                                                   0,5       9                                                      29           0,1       0                                                                    0,25     5                                                                   0,5       9                                                      30           0,1       0                                                                    0,25     7                                                                   0,5       10                                                     ______________________________________                                    

Various modifications of the products and processes of the invention maybe made without departing from the spirit or scope thereof and it shouldbe understood that the invention is intended to be limited only asdefined in the appended claims.

What we claim is:
 1. A syn isomer compound having a formula selectedfrom the group consisting of ##STR57## wherein A' is selected from thegroup consisting of hydrogen, alkali metal, alkaline earth metal, --NH₄,magnesium, non-toxic, pharmaceutically acceptable organic amine and aneasily cleavable ester group R'₂ is selected from the group consistingof alkyl of 1 to 6 carbon atoms optionally interrupted with an oxygenatom, alkenyl and alkynyl of 2 to 6 carbon atoms and aralkyl of 7 to 12carbon atoms optionally substituted with at least one member of thegroup consisting of carboxy, amino, aminoalkyl of 1 to 6 carbon atoms,alkyl of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms anddialkylaminoalkyl of 1 to 6 carbon atoms, X¹ is selected from the groupconsisting of oxygen and sulfur optionally oxidized to sulfoxide orsulfone and R₁ " is an amino protective group.